1. Introduction
According to the National Health Interview Survey
(NHIS, 2023), new cases of chronic pain occur more frequently than
new cases of other common conditions, such as diabetes, depression
and high blood pressure (1). The
incidence of new cases of chronic pain is estimated at 52.4 cases
per 1,000 individuals per year, compared to 7.1 for diabetes, 15.9
for depression and 45.3 for hypertension (1). Globally, pain affects billions of
individuals each day. A previous meta-analysis of 25 studies
estimated that the prevalence of chronic widespread pain across
cultural groups in Europe, Asia and the Americas ranged from 0 to
24% (2). Research has demonstrated
that women report pain more frequently than men, that pain
prevalence increases with age, and that cases of pain tend to be
higher in rural than urban areas (3). A recent global survey involving 52
countries, based on data from the 2002-2004 World Health Survey
(WHS), found that the prevalence of moderate to extreme pain among
adults aged ≥25 years was 27.5%. This prevalence ranged from a
minimum of 9.9% in China to a maximum of 50.3% in Morocco (3). Consequently, chronic pain represents a
significant public health burden. Pain can generally be categorized
into four main types: Acute pain, nociceptive pain, chronic pain
and neuropathic pain (4). The
present review focuses primarily on nociceptive, acute and chronic
pain, with selected examples of neuropathic pain provided where
relevant.
The spinal cord serves as the central highway for
transmitting ascending and descending information to various body
segments, very similar to a network connecting distinct towns or
counties. Each spinal cord segment contains a complex network of
afferent and efferent neurons, with dorsal root ganglia providing
the primary sensory relay, and these components are interlinked via
local interneurons and long-range projection neurons that
participate in ascending and descending tracts (Fig. S1). This integrated circuitry
enables precise sensory-motor coordination and ensures dynamic
communication with higher-order processing centers in the cortex,
thalamus, and brainstem, which are responsible for perception,
motor control and autonomic regulation (5).
Neuronal activity within this system arises from a
dynamic interplay among epigenetic regulation, genetic programming,
cellular physiology, and environmental influences. These
interactions encompass the electrical and chemical activities of
neuronal membranes, including the receptors, ion channels,
transporters and signaling molecules. Neuronal gene expression is
constantly modulated by intra- and extracellular stimuli, such as
stress, learning processes, emotional experiences and exposure to
toxins, each of which can trigger epigenetic modifications. These
modifications are essential to the plasticity of the nervous
system, enabling both structural changes e.g., alterations in
dendritic spine density and functional adaptations e.g., long-term
potentiation and long-term depression (6). Epigenetic modifications are crucial
for these long-term neural adaptations, influencing processes, such
as pain perception, learning, memory consolidation and
susceptibility to neurological disorders. Environmental factors
including stress, nutrition and exposure to toxins, which are
skyrocketing due to climate change (7), further contribute to remodeling the
epigenetic landscape, promoting maladaptive plasticity and chronic
pain sensitization.
Key epigenetic mechanisms, namely DNA methylation,
histone modification and non-coding RNAs, function as molecular
switches or dimmers, altering gene expression without changing the
DNA sequence. In the nervous system, these modifications help
encode experiences, such as pain or learning events, into
long-lasting changes in neuronal function and connectivity
(8,9).
The dorsal horn of the spinal cord is a critical hub
for processing nociceptive (pain-related) signals and exemplifies
how environmental and molecular influences shape neuronal
plasticity. As the first central relay for sensory input from
peripheral nociceptors (nociceptive neurons), the dorsal horn
integrates signals through a finely tuned balance of excitatory and
inhibitory neurotransmission. Following nerve injury or
inflammation, this balance is often disrupted, resulting in central
sensitization, a hyperexcitable state of dorsal horn neurons (DHNs)
that underlies phenomena such as allodynia and hyperalgesia
(10). Epigenetic alterations are
key contributors to these changes in neurotransmission.
Modifications in DNA methylation, histone acetylation and
non-coding RNA expression within dorsal horn neurons and glial
cells regulate the transcription of genes involved in synaptic
signaling, neuroinflammation and plasticity (11,12).
For example, the enhanced expression of glutamatergic receptors or
pro-inflammatory cytokines, along with impaired inhibitory
signaling, can be epigenetically programmed in response to
persistent nociceptive input or environmental stressors (13,14).
Emerging epigenetic-based therapies, such as histone deacetylase
(HDAC) inhibitors, microRNA (miRNA/miR) modulators and DNA
methylation blockers, which are discussed in the article, are
currently under investigation for their potential to reverse
chronic pain states by restoring homeostatic gene expression and
reducing pain hypersensitivity (15).
Despite these advances, the specific epigenetic
regulation of ion channels in nociceptive neurons remains
insufficiently understood. Ion channels, including voltage-gated
sodium, potassium, and calcium channels, transient receptor
potential channels (TRP channels) and acid-sensing ion channels,
are critical for generating and propagating pain signals. However,
how epigenetic modifications influence their expression and
function in the spinal cord remains largely unexplored. The present
review represents a first step toward consolidating current
knowledge on the epigenetic modulation of pain highways or channels
in the spinal cord and identifying key gaps to guide future
research. The present review begins with an overview of spinal cord
structure, cellular composition, and nociceptive pathways, followed
by a detailed examination of the known epigenetic mechanisms
regulating ion channels expression in the context of pain.
2. Spinal cord length is unparalleled with
that of the vertebral column after birth
The spinal cord begins at the medulla oblongata in
the rostral (upper) region at the level of the foramen magnum and
extends down to approximately the lumbar, L1-L2 vertebral level in
adults, where it tapers into the conus medullaris (Fig. S1A). Beyond the conus medullaris,
the cauda equina (‘horse's tail’) consists of a bundle of spinal
nerves that continue to the lower vertebrae, including the
coccygeal region (Fig. S1B)
(16). During fetal development,
the spinal cord is aligned with the vertebral column. However,
after birth, its growth slows while the vertebral column continues
to elongate, resulting in the spinal cord terminating earlier
within the vertebral canal, a process known as the ascent of the
spinal cord. By 15 weeks of gestation, the cord reaches the lower
border of the sacral S1 vertebra; by 6 months, it reaches the L4
level; and by full term, it typically aligns with the lower border
of L3. These levels vary slightly between male and female fetuses.
In recent research performed on human fetuses, 16 fetuses exhibited
a spinal cord termination at level L2, followed by 8 fetuses at the
L3 level and 6 fetuses at the L4 level. Comparing male vs. female
fetuses, out of 11 male fetuses, 8 fetuses had spinal cord
termination at the L2 vertebra level, two at the L3 level, and one
fetus at the L4 level. In female fetuses, eight had a spinal cord
termination at the L2 level, six at the L3 level and five at the L4
level (17).
3. Mapping the spinal cord: Spinal nerves
and segments
The spinal cord is covered by three layers of
meninges: The dura mater, the arachnoid mater and the pia mater
(Fig. S1C). In a transverse
section of the spinal cord, the outer layer consists of white
matter, while the inner layer is made up of gray matter that
surrounds ependymal cells lining the central canal, which is filled
with cerebrospinal fluid (18).
This central canal is continuous with the fourth ventricle-part of
the cerebral ventricular system (19). The ratio of white to gray matter
varies along the rostro-caudal axis of the spinal cord. At the
lower levels, the ratio between gray matter and white matter is
greater than in higher levels, mainly as lower levels contain less
ascending and descending nerve fibers. Similarly, at the higher
levels, the ratio of white matter to gray matter is higher as
ascending tracts gain fibers at each successive level and
descending tracts lose fibers (20).
The human spinal cord consists of 31 segments: Eight
cervical, 12 thoracic, five lumbar, five sacral and one coccygeal.
These 31 segments are defined by the 31 pairs of spinal nerves that
connect various body segments to the brain. Each spinal nerve exits
through the intervertebral foramen, the opening between two
adjacent vertebrae (Fig. S1). In a
transverse section, the spinal cord has an H-shaped or
butterfly-like appearance, featuring four protrusions, the dorsal
and ventral horns, that extend dorso- or ventrolaterally toward the
attachment zones of the dorsal and ventral root fascicles of each
spinal nerve tracts (16) (Fig. S2).
Spinal nerves are categorized based on their
vertebral alignment: Cervical (C1-C8), thoracic (T1-T12), lumbar
(L1-L5), sacral (S1-S5) and coccygeal (Co1) (Fig. S1). Each spinal nerve is a mixed
nerve composed of both sensory (afferent) and motor (efferent)
fibers. These nerves consist of fascicles of nerve fibers that
innervate specific regions of skin and muscles. Each such region
corresponds to a single segment, and the area of skin supplied by
peripheral nerve fibers originating from a single dorsal root
ganglion (DRG) is known as a dermatome (20).
Each spinal segment is characterized by dorsal roots
that enter the spinal cord and ventral roots that exit it. The
dorsal roots contain primary afferent neurons, carrying information
from the periphery, the cell bodies of these neurons are located in
the DRGs. By contrast, the ventral roots of spinal nerves carry
efferent neurons, with their cell bodies found in the spinal gray
matter (16,20). Immediately after leaving the
intervertebral foramina, spinal nerves divide to produce a thin
dorsal ramus (supplies the muscles and skin of the back) and a much
larger ventral ramus (supplies the muscles and skin of the front of
the body and limbs) (Figs. S1C and
S3) (16). The DRG is approximately the size of
a tiny peanut. The DRG is an enlargement of the dorsal root that
houses somata (cell bodies) of primary sensory neurons; an average
of 15,000 neurons are present in the DRG, although these numbers
vary with their location; for example, there are 60,000 neurons at
C5 and 100,000 at the C7 level (21,22).
Afferent fibers, originating from the DRG, carry sensory
information (touch, pain, temperature and proprioception) from
peripheral receptors into the dorsal horn. Ventral (anterior) horns
house the cell bodies of lower motor neurons (alpha motor neurons
and gamma motor neurons), which send efferent fibers through the
ventral root to innervate skeletal muscles (16) (Fig.
S2).
4. Spinal Golgi neurons
Across all levels of the spinal cord, there are four
types of neurons in spinal cord: Afferent neurons (sensory),
efferent (motor) neurons, interneurons, and those interneurons that
relay long-range signals to the central nervous system (CNS) and
peripheral nervous system (PNS), also known as projection neurons
(23,24). Due to the morphological and
functional diversity of spinal neurons in the spinal cord, it is a
challenge to classify or categorize these. In general, a number of
nerve cells in the CNS and PNS are Golgi type or multipolar, as
discovered by Camillo Golgi: Golgi type I and Golgi type II neurons
(21).
Based upon their location, Golgi type I cells, also
known as projection neurons or root cells due to their axons
extending to the brain, ranging from several millimeters to up to a
meter in length are primarily located in laminae I, III-VIII and X
of the dorsal horn, where they play key roles in integrating and
relaying nociceptive, mechanosensory and autonomic signals
(Fig. S2). Golgi type I cells are
very few in the lamina II at lumbar levels and they are also part
of the lateral spinal nucleus, where they contribute to long-range
sensory pathways, such as the spinothalamic tract (STT) and
spinoreticular tract (SRT) (24-27)
(Fig. S2). Many dorsal horn
projection neurons, including those in lamina I, have axons that
cross the midline and travel rostrally in the contralateral white
matter to terminate in various brainstem and thalamic nuclei via
the anterolateral tract, forming a collection of ascending pathways
that are thought to underlie nociception and thermoreception
(23) (Fig. S3). The pain-, temperature- and
itch-relevant information that originates throughout the body is
conveyed to the spinal cord and from the face and head via the
medullary trigeminal nucleus caudalis (24). The projection neurons or root cells
that contribute their axons to the ventral roots are of two types:
i) Somatic efferent root neurons, which innervate the skeletal
musculature; and ii) the visceral efferent root neurons, also known
as preganglionic autonomic axons, which send their axons to various
autonomic ganglia (20).
Golgi type II neurons, interneurons or column cells
have short axons confined to a local area, where they arborize
locally, mainly within the gray matter of the spinal cord (23) (Figs.
S2 and S3). They include
virtually all of the neurons in lamina II, and most of those in
laminae I and III of dorsal grey horn (23). Some column cells send their axons up
and down the cord to terminate in gray matter close to their
origin, or to nearby spinal segments and are known as
inter-segmental association column cells. Other column cell axons
terminate within the segment in which they originate and are known
as intra-segmental association column cells (20,28).
5. Rexed laminae
The journey through the gray matter of the spinal
cord is perplexing. At every less-than-millimeter distance, there
are layers, or laminae of neurons, with varying morphologies,
composition, as well as neurons that respond differently to
neurotransmitters. The gray matter also contains both interneurons
and projection neurons as aforementioned. Rexed (29,30)
was the first to categorize the spinal cord of cats on the basis of
its cytoarchitecture in different zones. Rexed (29) divided the grey matter of the cat
dorsal horn into a series of parallel laminae based on variations
in the size, packing density and the functional role of neurons.
This classification scheme has since been applied to other species
(29). The gray matter of the
spinal cord has been divided into ten laminae or layers with
different complex functions (Fig.
S3), for example, lamina I is only 800 µm in diameter and is
full of uniformly packed large poorly ramified neurons (31). Laminae I to IV, in general, are
related with exteroceptive sensation and comprise the dorsal horn.
Lamina I is also known as the marginal nucleus of spinal cord (or
posteromarginal nucleus) and lamina II as the substantia
gelatinosa; these play central roles in nociception and
thermoregulation, projecting to the diencephalon (23) (Table
I and Fig. S3). The lamina II
is further divided into outer (IIo) and inner (IIi) parts, with the
inner having a somewhat lower density of neurons (23). Interneurons primarily inhabit lamina
I to lamina III (32). Laminae V
and VI are concerned primarily with proprioceptive sensations
(Table I). Lamina VII is equivalent
to the intermediate zone and acts as a relay between muscle
spindles to midbrain and cerebellum, and laminae VIII-IX comprise
the ventral horn and contain mainly motor neurons (20) (Table
I). The axons of these neurons innervate mainly skeletal
muscle. Lamina X surrounds the central canal and contains neuroglia
(Table I and Fig. S3).
 | Table IRexed laminae overview. |
Table I
Rexed laminae overview.
| Rexed lamina |
Cytoarchitecture | Stimuli/functional
role |
|---|
| I | Thin layer at the
dorsal horn tip (marginal zone/posterior marginalis nucleus);
contains multipolar and fusiform cells. | Processes
painful stimuli: heat, pinching, cold; projects to
contralateral spinothalamic tract. |
| II | Substantia
gelatinosa of Rolando; densely packed interneurons. | Modulates
nociceptive pain; involved in gating noxious stimuli to higher
laminae |
| III | Dense network of
neurons receiving Aβ input; includes dendrites from laminae IV-VI;
part of nucleus proprius. | Processes light
touch, proprioception, nociception, and thermoception. |
| IV | Thickest lamina;
lower cell density, larger cells; part of nucleus proprius. | Processes
non-noxious stimuli, especially light mechanical touch, contributes
to spinothalamic projections. |
| V | Broad zone with
medial/lateral parts; receives Aβ, Aδ and C fibers; projects to
brainstem and thalamus via the contralateral and ipsilateral
spinothalamic tract. Moreover, descending corticospinal and
rubrospinal fibers synapse upon its cells. | Conveys
nociceptive and visceral pain, as well as proprioceptive
input. |
| VI | Prominent in
cervical/lumbar regions, contains interneurons and spinocerebellar
pathways. | Proprioceptive
processing; involved in reflex arcs. |
| VII | Zona
intermedia/intermediolateral nucleus; relays between afferents and
autonomic outputs. | Relay for visceral
motor neuronal output and cerebellar pathways. |
| VIII | Base of ventral
horn; receives descending vestibulospinal and reticulospinal
input. | Modulates motor
output via gamma motor neurons. |
| IX | Groups of large α
and small γ/β motor neurons; larger in cord enlargements. | Main site of
somatic motor neuron output. |
| X | Surrounds central
canal; forms the gray commissure. | Contains
interneurons and neuroglia; site of axon decussation. |
6. Primary Golgi afferents in the spinal
dorsal horn
Primary afferents exhibit different types of axons:
Large myelinated Aβ fibers, which are low threshold
mechanoreceptors that respond to touch or hair movement; fine
myelinated, large in numbers Aδ fibers and unmyelinated C fibers
for nociception and thermoreception (23). The myelinated low-threshold
mechanoreceptive Aβ afferents arborise and extend from lamina inner
(IIi)-VI, whereas nociceptive and thermoreceptive Aδ and C
afferents innervate lamina I and much of lamina II or substantia
gelatinosa (23,33) (Fig.
S2).
7. Neurochemical reception centers in the
spinal dorsal horn
The primary afferents are known for the expression
of various neurotransmitters such as substance P (also known as
neuropeptide P or SP-L1), (34,35),
glycine, glutamate, gamma-aminobutyric acid (GABA), serotonin and
endorphins. Based upon the neurotransmitter expression,
interneurons can be divided into two main classes: Excitatory
(glutamatergic) and inhibitory (glycinergic and GABAergic) neurons
(23). These cell bodies of
interneurons can be identified with specific antibodies. Substance
P is a major nociceptor marker, while GABA is present in ~25-40% of
neurons in laminae I-III (36,37).
Other neurochemical markers include somatostatin, neurotensin,
substance P and neurokinin B in glutamatergic neurons, and
neuropeptide Y and galanin in GABAergic neurons; enkephalin and
dynorphin occur in both (38,39).
Based upon substance P expression, nociceptive
unmyelinated C fibers are of two types: Peptidergic C fibers, which
express substance P and calcitonin gene-related peptide; arborise
mainly in lamina I and the outer part of lamina II (IIo) (32). Non-peptidergic C fibers bind the
lectin IB4 and express Mas-related G-protein coupled receptor
member D (MRGPRD), a sensory neuron-specific G protein-coupled
receptor in mice (32,40). In a previous study, the removal of
MRGPRD afferents in adult mice resulted in a selective loss of
sensitivity to noxious mechanical (but not thermal) stimuli
(41). Non-peptidergic C fibers are
mainly associated with the skin that innervate mainly epidermis
(42), whereas peptidergic fibers
innervate various other tissues as well as deeper regions of the
skin (35,43).
Additional markers include parvalbumin and neuronal
nitric oxide synthase in subsets of GABAergic/glycinergic neurons,
while calbindin, calretinin and protein kinase C (PKC)γ are largely
restricted to glutamatergic neurons (23,44-46).
Together, these molecular signatures form a neurochemical map of
the dorsal horn, reflecting the balance of excitation and
inhibition that ultimately determines nociceptive sensitivity and
pain perception.
8. Definition of pain
According to the International Association for the
Study of Pain, ‘Pain is an unpleasant sensory and emotional
experience associated with actual or potential tissue damage or
described in terms of such damage’. Two longstanding theories about
pain include the specific theory and the pattern theory (47). The specific theory posits that
particular receptors are responsible for transmitting pain signals
to designated areas of the central and peripheral nervous systems,
similar to how auditory and visual information is processed in the
brain. By contrast, the pattern theory suggests that there are
non-specific receptors for pain, and that there are no distinct
nerve endings dedicated solely to pain sensation. The skin contains
a diversity of sensory receptors that include touch, cold, warmth
and pain, which was the basis of von Frey's (1894) theory of
receptor sensitivity (48).
Sherrington (49) (1906) was the
first to state that all stimuli capable of injuring tissue be
labeled ‘noxious’ and coined the terms ‘nociception’ and
‘nociceptor’, to describe unique activity by selective afferents
(49). This established a common
understanding of the concept of pain-evoking stimuli (49).
These nociceptive signals are relayed from the
dorsal horn of the spinal cord to the higher brain centers was
first explained by the ‘gate theory’ described by Melzack and Wall
(47). This theory holds that the
nociceptor signals travel by Aδ and C fibers of peripheral nerves
through lateral spinothalamic tracts in the spinal cord to a pain
center in the thalamus (47).
Spinal cord is the gate control system that modulates afferent
sensory input from the skin before it evokes nociceptive response
(47). The inhibitory interneurons
of substantia gelatinosa (lamina II), play a key role in modulating
somatosensation, by selectively inhibiting primary afferent inputs
before these are transmitted to the brain through ascending
pathways. The activation of lamina-II or substantia gelatinosa by
touch receptors containing the large-myelinated afferents
suppresses T-cell activation and pain signals (25); however, the activation of Aδ and C
afferents transmit the pain signal (Fig. S2). Recent research has demonstrated
that both inhibitory and excitatory interneurons contribute to pain
signals through polysynaptic networks (25). The following section provides a
detailed explanation of nociceptive components.
9. Components of nociception
First-, second- and third-order
neurons in nociceptive pathways
As aforementioned, the spinal cord, with its
butterfly-shaped structure, serves as a highly intricate neural
highway. Its gray and white matter layers are anatomically divided
into dorsal, ventral and lateral horns which are attached to the
dorsal and ventral roots. These structures are essential for
transmitting somatosensory information, including nociception. For
the majority of somatosensory perceptions, first-order neurons
reside in the DRG for the body, or in the trigeminal ganglia for
the head and face. How do first order neurons relay action
potentials to the dorsal horn, comes from their physical shape.
These unique neurons in DRG receive inputs from peripheral sensory
receptors and transmit action potentials through their
pseudo-unipolar T-shaped axons, which bifurcate into a peripheral
process that innervates tissues, and a central process that enters
the spinal cord through the dorsal root (21,50,51)
(Fig. S3).
The first-order neuron axon stays on the same side
(ipsilateral) and its axon synapses with the cell body of the
second-order neuron that lies inside the spinal gray matter (dorsal
or ventral horns), or brainstem, depending on the specific sensory
modality. The second-order axon transmits nerve impulse (after
crossing over or decussation) to the third order neuron in the
thalamus that terminates in the somatosensory cortex located in the
postcentral gyrus of the parietal lobe of the cerebral hemispheres
(Fig. S3). The primary spinal
afferents that carry coarse touch/pressure, pain and temperature
information from limbs and trunk, terminate near their level of
entry into the spinal cord. They synapse with second-order neurons,
the axons of which decussate within a few segments and thereafter
form the key ascending spinothalamic tract (16).
Dorsal horn as a nociceptive hub
The dorsal horn is the major highway for receiving
primary afferents from various somites of the body containing skin
and deeper tissues of the body. The dorsal root ganglia are the
primary reception and transmission centers of these pain highways.
Dorsal horns hold diverse types of afferents for accurate, fast and
highly efficient neurotransmission. These are classified based upon
structure, for example, Golgi type-I projection neurons and Golgi
type-II interneurons as discussed in the previous section.
Additionally, these are also classified based upon their response
to specific sensory impulses: i) Low-threshold mechanoreceptors
activated by innocuous stimuli; ii) threshold neurons that react to
noxious stimuli; and iii) wide dynamic range (WDR) neurons, also
known as the convergent or multi-receptive neurons that receive
monosynaptic or polysynaptic synapses for both noxious and
innocuous stimuli (52). The WDR
neurons distributed through multiple laminae, exhibit graded
responses to both innocuous and noxious stimuli, including
mechanical, thermal and pruritic inputs (24,53-56).
Their response properties under the influence of opioids such as
morphine, particularly in trigeminothalamic tract neurons, exhibit
an altered sensitivity to pruritogens and algogens (57). Numerous opioid effects are also
mediated through superficial dorsal horn interneuron circuitry
(24). In rexed laminae 1-VIII, X,
except laminae II, the lateral spinal nucleus, deep and superficial
layers of lamina contain the projection nuclei for nociception
(1,2). Lamina I neuron projections are part of
spinothalamic tracts that send signals to periaqueductal gray
matter (PAG), which is located around the cerebral aqueduct within
the tegmentum of the midbrain of the brain stem (58,59)
(Figs. S2 and S3). A series of studies of rat projection
neurons in the L4 segment in rats demonstrated that there were 400
projection neurons in lamina I, which can be retrogradely labelled
into the lateral parabrachial nucleus (LPb) or the caudal
ventrolateral medulla (CVLM) of the brain stem, with smaller
numbers projecting to the other sites (23,60-63)
(Fig. S3). Lamina IV-VI also gives
rise to spinothalamic tracts which project to the sensory ventral
posteromedial and posterolateral (VPM and VPL) thalamic nuclei, as
well as to the PAG (58) (Fig. S3). Lamina VII (intermediate zone)
gives rise to the spinoreticular tract, next to the STT (58,64).
Collectively, interneurons and projection neurons of the dorsal
horn contribute to several major ascending pain pathways. These
project to the nucleus of the solitary tract, dorsal column nuclei,
medial brainstem reticular formation, CVLM, LPb, PAG, thalamus,
hypothalamus, and ultimately, to the primary somatosensory cortex
of postcentral gyrus (23,24) (Fig.
S3).
Ascending and descending nociceptive
pathways
The white matter of the spinal cord contains both
ascending and descending nerve tracts that coordinate nociceptive
reception, conduction and modulation. Ascending tracts are
distributed throughout the dorsal, lateral and ventral columns.
These include the dorsal column-medial lemniscus pathway,
comprising the gracile fasciculus and the cuneate fasciculus, which
transmits fine touch, vibration and proprioception; the STTs of
lateral columns, which convey pain, temperature, crude touch and
pressure sensations; and the intermediary spinocerebellar tracts,
which relay unconscious proprioceptive information from muscles and
joints to the cerebellum (16)
(Fig. S3). The STTs are part of
the anterolateral system. Before synapsing in the substantia
gelatinosa (lamina II), their fibers travel briefly in Lissauer's
tract. After synapsing, the second-order neurons decussate and
ascend as part of the spinothalamic tract (65). The Lissauer's tracts synapse with
second-order neurons of different Rexed laminae. The lamina IV, V
and VI receive direct innervation from first-order afferents, as
well as from interneurons in lamina II. The axons of these
second-order neurons in laminae IV-VI (which are collectively known
as the nucleus proprius) cross the midline and ascend all the way
to the brainstem and thalamus in the anterolateral quadrant or the
contralateral half of the spinal cord. These fibers, together with
axons from second-order lamina I neurons, form the spinothalamic
tract, this overall pathway is also referred to as the
anterolateral system (66).
Indirect nociceptive pathways include the spinoreticular tract,
which projects from the anterolateral funiculus to the medial
brainstem reticular formation or crosses to the medial thalamus.
These pathways are collectively referred to as the SRT system,
which sends ipsilateral or bilateral projections to supraspinal
targets (24). The STT is the
direct nociceptive pathway, while the spinoreticular tract is the
indirect pathway (64). Hence, key
nociception nerve tracts include spinocervical tract (mainly in
cats) (67), dorsal column pain
pathway (68,69), STT and SRT, part of the
anterolateral system (24,70,71).
Descending tracts are found only in the lateral and
the anterior (ventral) columns (16). The principal descending tracts are
the lateral corticospinal tract and the rubrospinal tracts located
in the lateral column, reticulospinal vestibulospinal and the
anterior corticospinal tract (Fig.
S3) (20). Descending pathways
consist of neurons projecting from the sensory cortex to the
hypothalamus and amygdala. The neurons synapse in the PAG in the
midbrain. The PAG projects, via the rostral ventral medulla, down
the spinal cord. The descending tracts can modulate the
transmission of nociceptive information at the level of the dorsal
horn (72).
Electrophysiology and functional
specialization of nociceptive neurons
Pain-relevant electrophysiological studies in mice,
cats and monkeys have provided valuable insight into nociceptive
neurons. For example, lamina I projection neurons respond to
diverse stimuli: Some neurons react to heat, pinch and noxious cold
in monkeys (73), while others in
the STT population respond only to pinch and/or heat in cats
(74), exhibiting distinct
intrinsic properties. Certain STT neurons in cats (74) and monkeys (75) are exclusively activated by innocuous
cold, whereas a subpopulation of spinoparabrachial neurons in mice
responds solely to noxious cold. Chronic pain models further reveal
altered thresholds for innocuous stimuli. For instance, mechanical
thresholds decrease in the von Frey filament test on naïve mice; in
cases of thermal allodynia, animals with chronic pain react to cold
stimuli below the usual nociceptive threshold. These behavioral
outcomes mirror human pain sensitization and likely involve
synaptic changes in dorsal horn circuits, as well as long-term
physiological and epigenetic modulation of interneurons, projection
neurons and supraspinal centers. While epigenetic mechanisms, such
as histone acetylation or DNA methylation, are increasingly
implicated in nociception, their precise roles remain
underexplored. A more in-depth understanding may pave the way for
targeted interventions.
10. Roads that lead to the pain
highways
Ion channels control the major flow of ions across
the plasma membrane of neurons that generate and propagate action
potentials. Three sodium ions are moved out of the cell for every
two potassium ions moved in; this maintains the resting membrane
potential of neurons. Due to this distribution of ions, there is a
more negative charge inside the cell, which maintains the closure
of voltage-gated ion channels in the plasma membrane during
negative resting potential. Depolarization occurs when the charge
inside the cell becomes less negative when it receives a sensory
stimulus or is triggered by a neurotransmitter that generates an
action potential (20). With the
opening of the sodium-potassium pump, the voltage-gated sodium
(Na+) and calcium channels that had been closed while
the cell was at resting potential are opened in response to an
initial change in voltage (76).
Neurons function as transducers that convert synaptic inputs into
output signals in the form of action potentials, which then
propagate information to other neurons. This transduction process,
known as synaptic integration, is often highly complex and depends
on, among other things, the types and distribution of ion channels
that populate the neuronal membrane (77). Cells are full of ion channels, and
all of these play a role in nociception, particularly in DHNs,
DRGs, and ascending and descending tracts. Hence, experimental data
have demonstrated role of many of these channels in nociception,
e.g., voltage-gated sodium channels (VGSCs), potassium channels
(K+) and voltage-dependent calcium channels (VDCC), all
types L, N, P/Q,R T, TRP channels, acid-sensing ion channels
(ASICs) and purinergic P2X families (78). The epigenetics of sodium, potassium,
calcium and TRP channels will be discussed in the following
section.
11. Epigenetics of ion channels, an
unexplored frontier in nociceptive neurons
Epigenetics is defined as ‘the study of mitotically
and/or meiotically heritable changes in gene function that cannot
be explained by changes in the DNA sequence’ by Fincham (79). Chromatin remodeling, DNA
methylation, histone modifications and non-coding RNAs (ncRNAs)
play key roles in gene expression without changing DNA sequence
(80). Histones go through a
variety of post-translational modifications, such as lysine
acetylation and lysine deacetylation, lysine methylation and
arginine methylation, phosphorylation, propionylation and
butyrylation, biotinylation, proline cis-trans isomerization,
ubiquitylation, glycosylation, citrullination, SUMOylation, ADP
ribosylation, deamination and crotonylation. Histone-modifying
enzymes are classified into three categories: i) Writers: Histone
acetyltransferases and histone methyltransferases; ii) erasers:
HDACs and histone lysine demethylases (KDMs and Jumonji families);
and iii readers: Proteins that recognize these histone
modifications (bromodomain, chromodomain and Tudor domain)
(81). The methylation of histone
H3 lysine residues occurs at positions K4, K9, K27, K36 and K79,
while histone H4 is methylated at K20. Specific patterns of histone
methylation are associated with distinct gene regulatory outcomes.
For instance, H3K4, H3K36 and H3K79 methylation are typically
linked to transcriptionally active genes, whereas H3K9, H3K27 and
H4K20 methylation are associated with transcriptional repression
(82).
Beyond histone modifications, DNA methylation also
plays a crucial role in gene regulation. While the majority of the
genome is methylated, CpG islands, which are typically 1kb in
length and often include promoter or RNA polymerase II binding
sites, are usually unmethylated in the majority of somatic cells.
Unmethylated CpG islands, found in euchromatin, are associated with
actively transcribed genes, whereas methylated CpG islands in
heterochromatin are linked to transcriptionally repressed genes
(80).
Another key epigenetic mechanism is RNA interference
(RNAi), a process in which noncoding RNAs regulate gene expression
at multiple levels, including mRNA degradation, translation
inhibition, RNA splicing, chromatin remodeling and chromosome
segregation (83). From zygote
implantation to adult tissue homeostasis, ncRNAs influence and
regulate key processes, such as cell proliferation, differentiation
and stress responses, fat metabolism in fruit flies, neuronal
patterning in nematodes, the functions of hematopoietic cells, and
differentiation in mammals, root, stem and leaf formation in plants
(84,85). ncRNAs are increasingly recognized as
critical players in numberous medical conditions, including
nociception.
The discovery of ncRNAs dates back to the 1950s,
when ribosomal RNA (rRNA) and transfer RNA (tRNA) were described by
Palade (86) and Hoagland et
al (87). The first miRNA,
micF (93 nt), was discovered in Escherichia coli in
1984(88). Another notable ncRNA,
6S RNA (184 nt), was detected in 1967(89); however, it was not appreciated until
its function to inhibit transcription by binding the sigma 70
subunit of RNA polymerase was elucidated (90). In humans, the lncRNA H19 was
reported in 1990 as one of the earliest imprinted transcripts
(91). In the context of
nociception, ncRNAs modulate pain processing at multiple levels of
the nervous system, including peripheral sensory neurons,
interneurons within the dorsal horn, ascending spinothalamic
pathways and central somatosensory circuits (92,93).
ncRNAs represent a structurally and functionally
diverse class. Long ncRNAs (lncRNAs), typically, >200
nucleotides in length, regulate gene expression through
transcriptional, post-transcriptional and epigenetic mechanisms.
lncRNAs are categorized into five types: i) Sense; ii) antisense;
iii) bidirectional; iv) intronic; and v) intergenic (94). Circular RNAs (circRNAs), a more
recently characterized group, form covalently closed loops lacking
5' caps and 3' poly(A) tails. Generated by non-canonical
back-splicing or exon skipping of precursor mRNAs, circRNAs are
enriched in the cytoplasm and often function as miRNA sponges or
protein scaffolds (94). Both
lncRNAs and circRNAs are known for competing with the target genes
of miRNA binding sites, thereby acting as competing endogenous RNA
(ceRNAs) (94).
Beyond structural diversity, ncRNAs are also
regulated by chemical modifications. To date, >160 types of RNA
modifications have been identified (95). Among these,
N6-methyladenosine (m6A) is the most
prevalent and extensively studied. m6A influences almost
all aspects of RNA metabolism, including splicing, processing,
transport, translation and stability. This modification is enriched
near the termination codon and in the 3' untranslated regions
(3'UTRs) of mRNAs (96-98).
In mammals, m6A occurs at a frequency of ~0.1-0.4% of
adenosines, corresponding to ~3-5 m6A sites per mRNA (99-101).
The deposition and removal of m6A are mediated by a
dynamic set of enzymes. The core methyltransferase complex (METTL,
‘writers’) includes METTL3, METTL14 and Wilms' tumor1-associating
protein, while demethylases (‘erasers’) include fat-mass and
obesity-associated protein (FTO) and AlkB Homolog 5, RNA
demethylase (ALKBH5) and YTH domain family proteins
(m6A-binding protein YTH domain family) and insulin like
growth factor 2 mRNA binding proteins as readers (94). Together with m6A-binding
proteins (‘readers’), these regulators play essential roles in
neuronal development, memory consolidation, CNS homeostasis and
pain processing (102). For
example, peripheral nerve injury upregulates FTO expression
in DRGs, reducing m6A modification on euchromatic histone-lysine
N-methyltransferase 2 (Ehmt2) mRNA, which codes for G9a
histone methyltransferase (103).
The downregulation of FTO rescues the loss of m6A and
alleviates nerve injury-induced hypersensitivity, indicating that
FTO contributes to neuropathic pain in an
m6A-dependent manner (103).
Similarly, in a model of inflammatory pain induced
by complete Freund's adjuvant (CFA), the downregulation of
METTL3 and the m6A reader, YTHDF2,
stabilized the upregulation of ten-eleven translocation
methylcytosine dioxygenase 1 (TET1) mRNA in spinal cord
neurons, thereby contributing to chronic inflammatory pain
(102). METTL3 together with
YTHDF2 coordinately regulated spinal neuron activation by mediation
of the TET1/signal transducer and activator of transcription 3
(STAT3) axis (102). The
overexpression of METTL3 reversed the increase in the levels
of spinal STAT3 and C-FOS (a neuron activation marker) on day 3
following the injection of Lenti-METTL3 in mice with CFA-induced
inflammatory pain. The loss of spinal METTL3 was associated with a
loss of global m6A levels in spinal RNAs, highlighting
the crosstalk between RNA methylation and other epigenetic
mechanisms under conditions of chronic pain (102). TET1 is known for its role in
converting 5-methylcytosine in DNA to 5-hydroxymethylcytosine, and
it has been found to be upregulated in both inflammatory and
neuropathic pain states (104).
Elevated levels of TET1 promote the expression of genes, such as
STAT3, brain-derived neurotrophic factor (BDNF) and metabotropic
glutamate receptor subtype 5 (mGluR5). STAT3, BDNF and mGluR5 drive
neuronal sensitization (104-106).
The genetic knockdown of spinal TET1 prevents this upregulation and
alleviates nociceptive hypersensitivity, underscoring the interplay
between RNA modifications and DNA hydroxymethylation in pain
pathophysiology.
Based on findings from whole-genome and
transcriptome sequencing projects, as well as RNAi-based
experiments, three main classes of small regulatory RNAs have been
identified: miRNAs, small interfering RNAs (siRNAs) and
Piwi-interacting RNAs (piRNAs). The present review focuses
exclusively on miRNAs in nociceptive processing, while also
highlighting recent advances in the fields of lncRNAs, circRNAs and
m6A modifications. The following section addresses
epigenetic mechanisms, including DNA methylation, histone
modifications and miRNA regulation and m6A modifications
in the modulation of nociceptive ion channels.
12. Epigenetic mechanisms of voltage-gated
sodium channels
Structure and function of VGSCs
This journey begins with the epigenetics of VGSCs.
Sodium and potassium channels are the primary channels responsible
for maintaining the resting potential of neuronal membranes. Upon
stimulation, these channels undergo conformational changes, cycling
through resting, activated and inactivated states, that lead to
membrane depolarization and action potential generation (107). Sodium channels are of two types,
VGSCs that are present in all types of body cells, and the
epithelial sodium channels only present in skin and kidney cells
(107). However, there are
variations, namely
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and
nicotinic sodium channels that are both ligand-gated (107). In most cases, sodium channels are
one of the first opened channels in response to depolarization,
which results in the influx of sodium ions, increasing the positive
charge inside the cells, which results in an action potential and
the release of neurotransmitters. The VGSCs are known to have two
gates, an activating gate that is dependent upon voltage and an
inactivating gate that is time-dependent. These gates work in
tandem to ensure a brief Na+ influx. The activating gate
opens, bringing Na+, and the inactivating gate closes,
stopping the flow of Na+ ions. After briefly opening,
VGSCs inactivate, halting sodium flow despite ongoing stimulation.
The channel will remain unable to open again until the cell
repolarizes to a threshold voltage that varies depending on the
cell type. This prevents a constant, unstoppable flow of
Na+ and depolarization inside the cell. This flow is
under a higher signal and physiological balance caused by the
interaction of other membrane proteins, cytoskeletal proteins,
changes in concentration of ions, extracellular proteins, and
neurotransmitters. This mode of VGSCs is critical in maintaining
the same threshold of stimulus; however, this can change in case of
mechanical, chemical and thermal stimuli.
Sodium-channel proteins in the mammalian brain are
composed of a complex of a 260 kDa α-subunit in association with
one or more auxiliary β-subunits (β1, β2 and/or β3) of 33-36 kDa
(108). Of note, nine types of
α-subunits (Nav1.1-Nav1.9) have been
functionally characterized, and a tenth related isoform
(Nax) may also function as a Na+ channel.
These types differ in their activation threshold, rate of
inactivation and sensitivity to tetrodotoxin (TTX), a neurotoxin
(107,109). Nav1.1,
Nav1.6, and Nav1.7 are fast-inactivating,
TTX-sensitive (TTX-S) channels, whereas Nav1.8 and
Nav1.9 are slow-inactivating, TTX-resistant (TTX-R)
channels primarily expressed in adult peripheral sensory neurons
(110). The TTX-S channel
Nav1.3 is predominantly expressed in embryonic sensory
neurons, but is upregulated following traumatic or metabolic nerve
injury in rodent DRG neurons (111).
Role of VGSCs types in nociceptive
neurons
Nociceptive pain is caused by tissue or nerve
injury-whether mechanical, thermal or chemical, whereas neuropathic
pain results from lesions or disease affecting the PNS or CNS
(112). The family of sodium
channels has five isoforms: Nav1.3, Nav1.6,
Nav1.7, Nav1.8, and Nav1.9
(Fig. S4). All sodium channels
have been found in both nociceptive and neuropathic pain. For
example, TTX-R channel Nav1.8 mRNA has been shown to be
upregulated in an established model of inflammatory pain, which was
induced by carrageenan injection into the hind paw (109). In addition, TTX-S channels
Nav1.3 and Nav1.7 exhibit an increased
expression with a parallel increase in TTX-S currents (109). SCN9A gene
(Nav1.7) mutations were detected in the II/S5 segment
(L858H) and the loop region between II/S4 and II/S5 (I848T), which
caused hyperpolarizing shift in the activation kinetics of the
mutated Nav1.7 channels (113) present on afferent and efferent
small nerve fibers (70), and
caused primary erythromelalgia (114). This rare, autosomal-dominant
peripheral neuropathic condition of erythromelalgia resulted in
episodic burning pain, edema and erythema (115), which may be treated with
intravenous lidocaine (116) and
future epigenetics-based therapies. Nav1.8 and
Nav1.9 are confined to nociceptive primary afferent
neurons (117-119).
Nav1.8 channels are preferentially found on
small-diameter neurons and, to a lesser extent, in medium- and
large-diameter cells; they are localized to the soma and the
terminal arbors of sensory neurons (120). Nav1.9 is generally
confined to small-diameter neurons (120,121). The current generated by
Nav1.8, also known as the sensory-neuron-specific
current, has a high threshold for activation (~-36 mV) and
steady-state inactivation. Unlike TTX-S channels, Nav1.8
activates and inactivates slowly, but recovers rapidly from its
inactivated state. This channel has a specialized function in
nociceptive sensory neurotransmission. Nav1.8 null
mutants exhibit analgesic behavior following noxious mechanical
stimulation (2). The majority of
sodium channels or highways are critically involved in the
transduction and transmission of nociceptive signals. However, the
epigenetics-led signals that contribute to the launching and
shutting of these channels have not yet been fully elucidated.
Epigenetic regulation of VGSCs in pain
pathways
The epigenetic regulation of sodium channels in
nociceptors remains largely unexplored, yet several key studies
have provided compelling insights. One of the most fascinating
epigenetic modifications is the restrictive silencer factor or
repressor element-1 (RE1)-silencing transcription factor (REST)
complex, also known as neuron-restrictive silencer factor (NRSF),
which plays a pivotal role in transcriptional repression during
neuropathic pain (122). REST
recruits HDAC through its corepressors, mSin3 and REST co-repressor
protein (CoREST), for repressing chromatin regions containing
neuron-restrictive silencer element (NRSE1/RE1) in target gene
promoters (123); for example, the
Scn10a gene for Nav1.8 sodium channel and the
Oprm1 gene for µ-opioid or MOP receptor in DRGs (Fig. S4) (124). As previously demonstrated, this
repression is particularly evident in models of neuropathic pain
caused by peripheral nerve injury, resulting in the downregulation
of Nav1.8 and MOP expression,
C-fiber hypoesthesia and the loss of peripheral morphine analgesia.
These neuropathic pain effects are reversed by the knockdown of
NRSF in male C57BL/6J mice, restoring both
Nav1.8 and MOP expression and
rescuing the analgesic response to morphine (124).
Histone modifications also play a critical role in
sodium channel expression. For example, the increased acetylation
of histone H4 at the Scn8a gene promoter (which encodes
Nav1.6) enhances transcription by promoting the
recruitment of phosphorylated STAT3 and its co-activator p300
(Fig. S4). This interaction is
enhanced by the exposure of DRG neurons to the pro-inflammatory
cytokine, TNF-α, thereby linking inflammatory signaling to sodium
channel upregulation (125)
(Fig. S4).
Beyond chromatin-level regulation, miRNAs
significantly contribute to the post-transcriptional control of
sodium channel expression during neuropathic pain. Both miR-96 and
miR-384-5p decrease the expression of Scn3A
(Nav1.3) (126,127) and alleviate neuropathic pain
(Table II) (126). miR-96 also decreases the in
vitro expression of Nav1.3 mRNA in
embryonic DRGs (126). miR-182 has
been shown to reduce Scn9A (Nav1.7) expression
(128), while overexpression of
miR-30b downregulated Scn3a, Scn8a, and Scn9a
in DRG neurons of the spinal cord, significantly alleviating pain
induced by spinal nerve ligation (SNL) or oxaliplatin
(antineoplastic drug) treatment (Table
II) (129-131).
Similarly, it has been shown that the overexpression of miR-183
inhibits Scn3a, Scn9a and Scn10a via the
TGFα-mediated CCL2/CCR2 signaling axis (Table II) (132). Additionally, miR-7a targets the
β2-subunit of voltage-gated sodium channels, and its overexpression
in injured DRG neurons normalizes the sustained hyperexcitability
of nociceptors (133) (Fig. S4).
| Table IIMicroRNAs regulating ion channels
involved in nociception. |
Table II
MicroRNAs regulating ion channels
involved in nociception.
| Type of ion
channel | MicroRNAs | Known signaling
molecules/pathways | (Refs.) |
|---|
| Sodium
channels | 1. miR-183 | - IL-6, IL-1β,
TNF-α and (-) TRPV1, | (126-133) |
| Nav1.3, Nav1.6 | | Nav1.3, Nav1.7 and
Nav1.8 | |
| Nav1.7, Nav1.8 | 2. miR-30b | - Nav1.3, Nav1.6,
Nav1.7 | |
| Nav1.9 | 3. miR-182 | - Nav1.7 | |
| | 4. miR-96, | - Nav1.3 | |
| | 5. miR-384-5p
(-) | - Nav1.3 | |
| Potassium
channels | 1. miR-183-5p, | Unknown | (142-145) |
|
Kv,
KCa | 2. miR-137 | Unknown | |
|
Kir,
K2P | 3. miR-17-92
clustera | Unknown | |
| Calcium
channels | 1. miR-103 | Unknown | 179-182,184) |
| L, N, P/Q, R,
T | 2. miR-32-5p | Unknown | |
| | 3. miR-124 | - MeCP2 | |
| | 4. miR-219 | - CaMKIIγ
and MeCP2 | |
| TRP channels | 1. miR-146a-5p | - NFKB | (182,240-247) |
| TRPV1, TRPV2, | 2. miR-381 | - HMGB1 | |
| TRPV3, TRPV4, | 3. miR-362-3p | - BAMB1 | (132) |
| TRPA1, TRPM8 | 4. miR155 or
miR221 | + SOCS1 via NF-KB
and p38 MAPK | (249-252) |
| | 5. miR-183 | - IL-6, IL-1β,
TNF-α | |
| | 6. miR-28-5p,
miR- | | |
| | 128-3p, miR-136,
miR- | - ZEB1, no channels
known? | |
| | 150, miR-200b, and
miR-429 | | (254,255) |
| | 7. miR-140,
miR-144 | - S1PR1, RASA1 | (253) |
| | 8. miR-23a | - CXCR4 and
TXNIP/NLRP3 | (256) |
| | 9. miR-216a-5p | - Wnt/β-catenin via
KDM3 | (247,260,261) |
| | 10. miR let-7b | + TLR7-TRPA1 | (258) |
| | 11. miR-141-5p | + TRPA1 (OXL) | (145,247,259,262-266) |
| | 12. miR-143,
miR-21, 133a, miR-134, miR-20a/b and Kcna2 | Unknown | |
Together, these findings underscore the
underappreciated complexity of epigenetic regulation in sodium
channel biology and highlight its potential as a therapeutic target
in the treatment of neuropathic and nociceptive pain.
13. Epigenetics of K channels
Functional overview of potassium
channels and their role in nociceptive neurons
Potassium channels are known for osmotic
regulation, hormonal secretion and electrical impulses in excitable
cells of muscles and neurons (134). Potassium channels are also known
for a conserved K channel amino acid signature sequence (135) that forms a structural element
known as the selectivity filter. This selectivity filter prevents
the passage of Na ions, but allows K ions to conduct across the
membrane at rates approaching the diffusion limit. This is the
hallmark of K+ channels: Almost perfect selectivity for
K+ ions over Na+ ions in the setting of very
high K+ conduction rates (136). Based upon their structure,
functional characteristics and pharmacologic sensitivity, K
channels are divided into four major families: Voltage-gated
(KV), calcium-activated (KCa), tandem pore or
two-pore domain (K2P) and the inward rectifier channels
(Kir) (137) (Fig. S5). Specific subtypes of K channels
respond to particular antinociceptive drugs, e.g., the
ATP-sensitive (KATP) members of the Kir
family, G-protein-regulated inwardly rectifying K+ channels
(Kir3), otherwise known as GIRK channels,
KV1.1 and the small-(SK) and large-(BK) conductance
calcium activated channels (138).
The presence of KV1.1 channels on small -iameter
trigeminal neurons projecting to the superficial layers of the
cervical DHN (139), on larger
diameter spinal DHNs, and also on Aδ and C visceral sensory
neurons, indicates that they play a role in nociception and pain
processing, warranting further investigation.
Epigenetic mechanisms regulating
potassium channels
As demonstrated in a previous study, in mice
lacking the gene for the Shaker-like voltage-gated potassium
channel KV1.1 alpha subunit, homozygous null (-/-)
animals exhibited significant hyperalgesia compared to their
heterozygous (±) and wild-type (+/+) littermates. Pain sensitivity
was measured using paw flick and hot plate assays, both of which
confirmed enhanced hyperalgesia and a preserved response to
morphine-induced antinociception (140). Neuropathic pain induced by
oxaliplatin (OXL) involves the downregulation of several
K+ channel subtypes, including members of the
K2P family (TREK and TRAAK). A single OXL administration
in mice has been shown to cause the transcriptional repression of
Kv and K2P channel genes through the action
of NRSF and its co-repressors, HDACs (Fig. S5). The knockdown of NRSF in the DRG
significantly mitigatesd OXL-induced downregulation of these
channels and prevents mechanical and cold hypersensitivity in mice
(141). The N-terminal domain of
NRSF binds HDACs and represses target genes, while the C-terminal
domain binds to CoRESTs, and further attracts HDAC1, HDAC2 and
methyl-CpG binding protein 2 (MeCP2) to promote and maintain
methylated CPG-dependent gene silencing (123). Additionally, miR-183-5p has been
shown to reduce neuropathic pain in a model of chronic constriction
injury (CCI) by suppressing expression of TREK-1, a K2p
channel (Table II) (142). In another study using a model of
CCI, Kv1.2 expression was downregulated in both the DRG
and spinal dorsal horn, which was associated with the increased
expression of miR-137(143). The
intrathecal injection of Kcna2 siRNA targeting Kv1.2 in
naïve rats led to significant mechanical and thermal
hypersensitivity. Conversely, blocking miR-137 in CCI rats
alleviated mechanical allodynia and thermal hyperalgesia, restored
Kv1.2 expression, normalized DRG neuronal excitability
and recovered Kv currents (143) (Fig.
S5). Similarly, the miR-17-92 cluster, which includes six miRNA
members, was found to downregulate K+ channels and
reduce outward potassium currents, particularly type A currents,
thereby contributing to mechanical allodynia in neuropathic pain
models (144) (Table II) (Fig. S5). Moreover, a conserved lncRNA,
named Kcna2 antisense RNA is commonly expressed in mammalian spinal
cord DRG neurons. During peripheral injury Kcna2 antisense RNA
promoter expression is increased via myeloid zinc finger protein 1
transcription factor and leading to the suppression of Kcna2
(Kv1.2) expression, enhanced neuronal excitability and the
persistence of neuropathic pain (145).
In summary, potassium channels are essential
regulators of neuronal excitability and play a pivotal role in
modulating nociceptive signaling. Their dysfunction is increasingly
attributed to epigenetic mechanisms, including transcriptional
repression by NRSF/HDAC complexes and post-transcriptional
regulation via specific miRNAs such as miR-137, miR-183-5p, the
miR-17-92 cluster and lncRNA Kcna2 (Table II). These regulatory processes
alter the expression and function of key K+ channel
subtypes, such as Kv1.1, Kv1.2, TREK and
TRAAK, leading to hyperexcitability and enhanced pain sensitivity.
Understanding these epigenetic modifications provides valuable
insights into pain pathophysiology and may provide novel
therapeutic strategies targeting the epigenetic landscape to
restore normal K+ channel function and alleviate
nociceptive and neuropathic pain.
14. Epigenetics of Ca channels (VDCCs)
Introduction to VDCCs and calcium
signaling
Calcium ions (Ca2+) act as universal
second messengers involved in a wide array of physiological and
pathological processes. Numerous intracellular events, such as
synaptic vesicle release, muscle contraction and electrical
signaling, rely on the maintenance of a precise calcium gradient,
largely regulated by VDCCs (146,147). The calcium concentration gradient,
and its epigenetic regulation via VDCCs, represents a potential
target for nociception-based and neuropathic pain treatments.
VDCC subtypes and their
localization
The VDCCs comprise four or five distinct α1, α2δ, β
and γ subunits, which are encoded by multiple genes. The largest of
all, the α1-subunit, contains the selective calcium ion pore, a
voltage sensor, and the binding site for selective high-threshold
VDCC blockers (148). A total ten
isoforms of the α1 subunit have been identified, which form the
basis for the most recent classification (149). The ten isoforms are grouped into
three major families according to their sequence homology. VDCCs
have also been grouped into six classes: L (Cav1.1,
Cav1.2, Cav1.3, Cav1.4), N
(Cav2.1), P/Q (Cav2.2), R (Cav2.3)
and T (Cav3.1, Cav3.2, Cav3.3)
according to their electrophysiologic properties and pharmacologic
susceptibility to specific blocking agents (146,148). These VDCC subtypes are
differentially distributed in neurons. The P/Q-type VDCCs are
located predominantly at presynaptic sites (150), N-type are found both pre- and
post-synaptically (151), while L-
and T-type channels are mainly located on the proximal dendrites
and soma of neurons, which are both post and pre/post synaptic
sites (152,153). In the dorsal horn of the rat, as
with other neuronal systems, such as cortical and hippocampal
pyramidal cells, high-threshold calcium currents can generate both
regenerative and plateau potentials, contributing to prolonged
neuronal activation (154-156),
which can cause both nociceptive and neuropathic pain.
VDCCs in nociceptive processing and
pain sensitization
As mentioned above in the context of VGSCs, due to
shift of resting membrane potential, the sustained plateau
potentials can result in nonlinear responses that enhance
nociceptive stimulation by L-type VDCCs (157,158). L-type channels have also been
implicated in inflammatory pain signaling, at least in models that
use chemical irritation of peripheral nerves and joints as a
nociceptive stimulus (148).
Blockers of N-type channels have demonstrated analgesic properties
against acute mechanical and thermal nociceptive stimulation in
several animal studies, P/Q-type channel blockers have been
reported to have inhibitory, facilitatory, or even no effects on
the responses of spinal neurons to nociceptive stimulation,
similarly R-type, T-type channels also contribute to nociceptive
signaling, although their roles are less well defined (148).
Mechanisms underlying persistent
nociceptive signaling
Nociceptive DHNs are capable of encoding persistent
noxious stimuli by generating prolonged after-discharges, which
often take the form of regenerative plateau potentials or sustained
depolarizations. These non-linear membrane responses enhance the
transmission of nociceptive signals to supraspinal centers
(158). Of note, two primary
mechanisms contribute to this phenomenon: First, the slow
inactivation of potassium channels, particularly in neurons
exhibiting hyperpolarized resting membrane potentials, reduces
outward potassium currents and delays repolarization. Second,
regenerative plateau potentials can be initiated near the resting
membrane potential, further increasing excitability (157,158).
In DHNs, as well as in cortical and hippocampal
pyramidal neurons of rats, these plateau potentials are primarily
mediated by high-threshold voltage-gated calcium currents, such as
those carried by L-type calcium channels. The sustained influx of
calcium prolongs depolarization and can shift the resting membrane
potential toward the threshold for action potential generation.
This voltage shift facilitates repetitive firing and contributes to
the nonlinear and amplified response properties observed in
nociceptive processing. Such mechanisms are considered to play a
pivotal role in central sensitization and the persistence of
chronic pain (148,158). All these mechanisms of calcium
gradient are regulated by epigenetics, such as DNA methylation,
histone modification and ncRNAs (15,159).
Epigenetic regulation of VDCCs
The epigenetic regulation of VDCCs remains a
largely unexplored area in nociceptive neurons, particularly in the
DRG. Calcium acts as a central second messenger orchestrating
diverse cellular processes, including gene transcription,
metabolism and apoptosis, and mediates its effects in part through
calcium-dependent enzymes such as histone deacetylases (e.g.,
HDAC4), Ca2+/calmodulin-dependent protein kinases (e.g.,
CaMKII) and calcineurin (160). These enzymes respond to
intracellular calcium fluctuations to alter chromatin structure,
DNA methylation patterns and transcription factor activity, thereby
modulating gene expression, which are vital for neuronal plasticity
and may underlie chronic pain mechanisms, which are underexplored
(161,162). For instance, calcium-activated
CaMKII can phosphorylate transcription factors such as CREB,
thereby influencing chromatin accessibility and transcriptional
expression (163). Conversely,
epigenetic modifications, including histone marks and DNA
methylation, can regulate the expression of key genes involved in
calcium homeostasis and signal transduction, such as VDCCs, pumps
and buffering proteins, establishing a reciprocal regulatory loop
(163). This bidirectional
interplay is increasingly recognized as a crucial mechanism in both
physiological processes and disease states, including nociception,
cardiac hypertrophy, neurodegenerative disorders and cancer.
Notable examples from stem cell differentiation and
cancer studies illustrate the functional relevance of
calcium-sensitive epigenetic modifications by signaling pathways.
The phosphorylation of histone H3 at Ser10 by JNK, initially
activated via MAPK signaling, has been implicated in gene
activation during stem cell differentiation (Fig. S6) (164). Similarly, during androgen receptor
[nuclear receptor and DNA binding transcription factor (165) activated signaling, the
phosphorylation of histone H3 at Thr6 by PKCβ blocks the
demethylation of H3K4 by lysine-specific histone demethylase 1A
(LSD1), promoting gene activation that contributed to prostate
cancer progression (166). LSD1
has also been shown to demethylate lysine 9 of histone 3 (H3K9)
during androgen receptor-activated gene expression, underscoring
the complex regulation of transcription by histone modifiers
(167). Notably, PKCβI
specifically localizes to androgen response elements (AREs) in the
promoters or enhancers of genes, such as kallikrein 2
(KLK2), FK506-binding protein 5 (FKBP5) and
transmembrane serine protease 2 (TMPRSS2), highlighting the
interconnection between calcium-linked signaling and epigenetic
modifications (166).
DNA methylation enzymes are also subject to
regulation by phosphorylation. For example, the phosphorylation of
DNA methyltransferase 1 (DNMT1) at Ser154 and Ser143 by
cyclin-dependent kinases and AKT1 (RAC, Rho family-alpha
serine/threonine-protein kinase) enhances its stability and
enzymatic activity (168,169), whereas the phosphorylation at
Ser146 by casein kinase 1δ/ε (CK1δ/ε) reduces its DNA binding
affinity (170). Similarly, the
casein kinase 2-mediated phosphorylation of DNMT3a diminishes its
ability to methylate repetitive elements and alters its
localization to heterochromatin (171), further linking calcium-associated
signaling to DNA methylation dynamics.
DNA methylation and histone
modifications in pain-related calcium channel regulation
The methylation of CpG islands within the promoter
regions of genes encoding calcium channel subunits (e.g.,
CACNA1C for Cav1.2 or CACNA1B for
Cav2.2) can lead to the long-term silencing or
upregulation of these genes in DRG neurons and spinal cord tissues
under pathological pain conditions. For example, chronic nerve
injury has been shown to be associated with hypomethylation of the
CACNA1C promoter, resulting in an increased expression of
Cav1.2 and enhanced calcium influx in sensory neurons (172) (Fig.
S6).
TET enzymes are well known for their role in DNA
demethylation. Their protein stability is regulated by
Ca2+-dependent proteases, specifically Calpain 1 and
Calpain 2. These proteases influence TET protein levels, thereby
modulating the DNA demethylation process (173). When intracellular Ca2+
concentrations are low, Calpain activity is reduced, leading to the
increased stability of TET1 and TET2 proteins and elevated levels
of 5-hydroxymethylcytosine (5hmC) (174), thus regulating calcium dependent
DNA demethylation. Similarly, histone acetylation levels at
promoter regions of calcium channel genes have been shown to
modulate their expression. HDAC inhibitors have been reported to
suppress the expression of N-type channels (Cav2.1) and
reduce nociceptive hypersensitivity in rodent models (159). Furthermore, membrane
depolarization-driven Ca2+ influx through L-type VGCCs
promotes enhancer RNA (eRNA) synthesis via increased H3K4me1
levels and CREB-binding protein (CBP) recruitment (175) (Fig.
S6). The amount of eRNA synthesis is positively
associated with the level of mRNA synthesis at nearby genes in
mouse cortical neurons. Calcium ions facilitate the phosphorylation
of MeCP2 by CaMKII, and trigger its dissociation from the
BDNF promoter and BDNF transcription, accompanied by reduced
H3K9 methylation, increased acetylation at the same site, and lower
CpG methylation frequency (176,177). Notably, mutations affecting MeCP2
phosphorylation have been linked to the regulation of dendritic
morphogenesis and spine maturation and are also associated with
Rett syndrome. Active enhancer DNA sequences exhibit H3K27
acetylation along with H3K4me1 methylation as compared to
inactive/poised enhancer elements containing H3K4me1 alone.
In another case, the inhibition of HDACs in primary
endothelial cells increased small conductance calcium-activated
potassium channel (KCa2.3) transcripts, KCa2.3 subunits and
subsequently, functional current was increased. The pan HDACi
trichostatin-A exposure in both human umbilical vein endothelial
cells and primary cultures of human intestinal microvascular
endothelial cells increased KCa2.3 protein expression (178).
ncRNAs
A growing body of evidence underscores the pivotal
role of ncRNAs, particularly miRNAs, in regulating calcium channel
expression and neuronal excitability in pain pathways. These
epigenetic regulators contribute to both the initiation and
maintenance of chronic pain states by modulating key components of
calcium signaling and VDCCs. For instance, miR-103 has been shown
to directly target the CACNA1C gene that codes for L-type
calcium channel Cav1.2(179). The downregulation of miR-103
results in an increased expression of Cav1.2 and
enhanced nociceptive signaling in chronic pain models (Table II) (179) (Fig.
S6). Likewise, the expression of miR-32-5p is suppressed by
histone methylation, leading to reduced targeting of the
CACNA1H gene that encodes Cav3.2, T-type calcium
channels in trigeminal ganglion neurons. This reduction in
miR-32-5p results in Cav3.2 upregulation,
contributing to trigeminal neuropathic pain (Table II) (180) (Fig.
S6). Another critical miRNA is miR-124, also known as the
CNS-specific miRNA (181,182). It is constitutively expressed in
the spinal dorsal horn neurons and plays a major role in
maintaining normal nociceptive thresholds. In a previous study
using a formalin-induced inflammatory pain model, peripheral
noxious stimulation led to the significant downregulation of
miR-124 expression (181). The
intravenous administration of a miR-124 inhibitor further
exacerbated pain behaviors, suggesting a protective role for
miR-124 in nociceptive modulation. Mechanistically, this
downregulation was associated with the increased expression of
pro-nociceptive targets, including MeCP2, a transcriptional
regulator modulated by CaMKs and other inflammatory genes (Table II) (181).
Another well-characterized CNS miRNA is miR-219,
which also targets CaMKIIγ. The deregulation of miR-219 is
also linked with mental disorders such as schizophrenia (183). The 3' UTR of CaMKIIγ
contains conserved miR-219 binding sites. In a previous study using
a model of CFA-induced chronic inflammatory pain, miR-219
downregulation in spinal neurons, led to elevated CaMKIIγ
and MeCP2 levels. This, in turn, promoted tge hypermethylation of
the miR-219 promoter, forming a feedback loop that perpetuated
nociceptive signaling (184).
Notably, miR-219 knockdown alone induced pain-like behaviors and
upregulated phosphorylated N-methyl-D-aspartate receptor (a subunit
of the NMDA-type glutamate receptor), highlighting its broader
impact on glutamatergic synaptic plasticity (Table II) (184).
Summary and future directions
The reciprocal association between calcium
signaling and epigenetic mechanisms constitutes a novel and
under-investigated axis in nociceptive neurons. Calcium influx
modulates key pro-inflammatory pathways, such as IRAK/TRAF6,
TLR4/NF-κB, CXCR4, TXNIP/NLRP3 inflammasome, MAPK, TNF-α and TLR5,
partly since calcium-dependent proteins, such as the CAMK
superfamily, regulate the activation of multiple transcription
factors, including CREB, ATF1, NF-κB, MeCP2, myocyte enhancer
factor 2 (MEF2) and serum response factor (163). By contrast, the phosphatase
Calcineurin regulates the activity of transcription factors such as
NFAT and MEF2 by dephosphorylation (163). DNA methyltransferases are
phosphorylated in response to calcium oscillations (140,141), and the CpG island methylation of
calcium channel gene promoters (e.g., CACNA1C) has been
observed in DRG neurons during chronic pain (172). TET demethylase activity also
fluctuates with calcium influx (173,174). Treatment with HDAC inhibitors can
enhance Ca²+-dependent eRNA synthesis by
increasing H3K4me1 levels and CBP recruitment (173). Moreover, MeCP2 phosphorylation by
CAMKII releases MeCP2 from the BDNF promoter, enhancing its
transcription. The suppression of N-type calcium channel
(Cav2.2) expression in the presence of HDACi reduces
hypersensitivity in rodent pain models. ncRNAs, such as miR-124 and
miR-219 function via MeCP2/CAMKs; miR-103 and miR-32-5p
downregulate Cav1.2 and
Cav3.2 expression respectively, thereby
attenuating nociceptive signaling (179-182,184).
Future studies that elucidate the precise molecular players in this
bidirectional regulatory system may reveal novel therapeutic
targets for chronic and treatment-resistant pain.
15. Epigenetics of TRP channels
Structure and function of TRP
channels
TRP channels represent the second largest family of
ion channels following the potassium channel family (185,186). While some TRP channels exhibit
weak voltage sensitivity, most are not truly voltage-gated as they
lack the hallmark voltage-sensing domain of classical voltage-gated
ion channels (187), thereby
challenging the longstanding view that TRP channel gating is
entirely voltage independent. Originally discovered in
Drosophila melanogaster as calcium transport channels by
Minke and Selinger (188), TRP
channels are currently recognized as polymodal, non-selective
cation channels that facilitate fluxes of calcium
(Ca2+), magnesium (Mg2+) and sodium
(Na+) (186). Due to
these cation fluxes, TRP channels play a crucial role in
intra-vesicular and extra-vesicular cycles during endocytosis and
exocytosis, and they are also found on lysosomes and mitochondria
(189,190). TRP channels facilitate the flow of
calcium ions that contribute to muscle contraction, gene
transcription, cell proliferation, neurotransmitter release,
apoptosis and fertilization (191). While the majority of TRP channels
are non-selective for cations, there are exceptions. For instance,
TRPV5 and TRPV6 are Ca2+-selective channels and are
expressed in epithelial tissues, such as the proximal small
intestine, distal nephron and placenta, where they are often
referred to as epithelial Ca2+ channels (EcaC) (192-195).
By contrast, TRPM4 and TRPM5 are only permeable to monovalent
cations.
TRP channels also serve as multimodal sensors that
detect diverse stimuli, including temperature, mechanical stress,
pH, osmolarity, light and chemical ligands, both endogenous and
exogenous. Their role in somatosensory perception spans species
from yeast to mammals (185,191,196). TRP channels are not only ion
channels; they are also involved in important signaling pathways,
such as the MAPK (197), TGF-β
(198), canonical NF-κB (199-201)
and AMP-activated protein kinase (AMPK) pathways (186,202-204).
Additionally, their activity is regulated through mechanisms, such
as transcription, alternative splicing, glycosylation and
phosphorylation, contributing to their functional diversity. Due to
their widespread expression across cell types and their ability to
function alone or synergistically with other ion channels, TRP
channels serve as critical cellular sensors. The dysfunction of TRP
channels has been implicated in a broad spectrum of diseases,
including gastrointestinal, cardiovascular, respiratory and
neurological disorders, as well as various types of cancer and
chronic pain syndromes. Given their ability to respond to diverse
stimuli, including temperature fluctuations, chemical compounds,
osmotic stress, mechanical forces, lipid signals, light, oxidative
stress, pH change and pheromones, a comprehensive ‘ion channel
signaling atlas’ could significantly advance the understanding of
TRP-mediated cellular responses and their pathological
consequences.
Role of TRP channels in
nociception
Noxious and neuropathic pain states are
characterized by heightened excitability of nociceptors, largely
driven by alterations in their ionic conductance properties. These
changes involve dysregulation of voltage-gated sodium channels
(e.g., NaV1.7, NaV1.8), calcium channels and various ligand-gated
and mechanosensitive ion channels, such as members of the TRP
family and ASICs. These ion channels facilitate the transduction
and propagation of noxious mechanical, thermal and chemical
stimuli. Based on their responsiveness, nociceptors can be
classified as unimodal-responding selectively to a single modality,
or polymodal, integrating multiple types of noxious stimuli.
As aforementioned, TRPs respond to mechanical,
chemical and thermal stimuli, due to an influx of non-selective
cations that depolarize neuronal cells and generate action
potentials (205). The majority of
TRP channels are expressed in primary afferent neurons, including
those found in the DRG, trigeminal ganglia and nodose ganglia
(205). TRP channels are key
components of nociceptive neuronal pathways, with TRPV1 being
particularly important. Originally identified as the vanilloid
receptor-1, TRPV1 is activated by heat, protons and vanilloid
compounds, such as capsaicin and resiniferatoxin (206). It serves as a key integrator of
thermal and chemical noxious stimuli. In invertebrates, TRPV1
homologue is involved in processes such as phototransduction,
mechanosensation, thermosensation and osmosensation. Several TRP
channels, including TRPV1, TRPV2, TRPV3, TRPV4, TRPA1 and TRPM8,
are found in DRGs. TRPV1, TRPV2, TRPV3 and TRPM8 function as
thermoreceptors, while TRPV4 and TRPA1 function as mechanoreceptors
(205). Additionally, TRPV1,
TRPV3, TRPM8 and TRPA1 serve as chemoreceptors, responding to
specific compounds, such as capsaicin, endocannabinoids, camphor
(207) menthol (208,209), mustard oil and cinnamon oil
(210,211). The TRPV1-4 subfamily exhibits
temperature-dependent ion currents, underscoring their role in
thermosensation.
In various chronic pain conditions, the expression
of TRPV1 is upregulated. Conversely, knockout animal models lacking
a functional TRPV1 gene fail to exhibit typical responses to
painful stimuli, highlighting its critical role in nociception
(205). TRP channels are also
highly expressed in trigeminal neurons and brain regions associated
with migraine pathogenesis, and transmit migraine-related pain
signals (212). Several studies
have highlighted their role in migraine, indicating their potential
as therapeutic targets (212). TRP
channels are constantly influenced by external and internal
physiological conditions (213).
Given their crucial role in nociception, the aforementioned
hallmark studies urge the investigation of the epigenetics of TRP
channels, which could pave the way for the development of new
therapies for chronic nociceptive pain.
Epigenetic regulation through histone
modifications
Both acute and chronic stress have been shown to
lower pain thresholds, increase visceral hypersensitivity and
elevate gastrointestinal motility, largely via activation of the
hypothalamic-pituitary-adrenal axis (214). Epigenetic research on the brain,
spinal cord and related disorders is still in its early stages.
However, previous studies have indicated that something perplexing
occurs under chronic and acute stress conditions, e.g., chronic
stress has been shown to downregulate the anti-nociceptive
endocannabinoid receptor 1 (CNR1, also known as CB1) in L6-S2 DRG
neurons (215). The TRPV1 channel,
which is a pro-nociceptive endovanilloid pain ion channel, is
upregulated in DRGs that innervate the pelvic organs, including the
colon, based on retrograde labeling and functional studies
(216,217). Both CNR1 and TRPV1 are
reciprocally regulated. For example, in a previous study, control
rats treated with serial injections of corticosterone exhibited a
significant increase in serum corticosterone levels, which was
associated with visceral hyperalgesia (217). This also included an enhanced
anandamide content, an increased TRPV1 expression and decreased CB1
receptor protein levels. Co-treatment with RU-486 prevented these
changes. Additionally, the exposure of isolated control L6-S2 DRGs
in vitro to corticosterone reproduced the alterations in CB1
and TRPV1 receptors observed in vivo, with these effects
also being prevented by co-treatment with RU-486 or
WIN55,212-2(217).
The alterations in TRPV1 and CB1 are likely driven
by epigenetic mechanisms, including chromatin remodeling, histone
modifications, DNA methylation and miRNA activity. One of the first
studies linking epigenetics with TRP channel expression revealed
that chronic stress increased levels of the histone
acetyltransferase EP300 gene expression, which promoted
histone acetylation at the Trpv1 promoter in L6-S2 DRGs and
enhanced TRPV1 expression. The knockdown of DNMT1 and
EP300 reversed these modifications and attenuated visceral
hypersensitivity (218) (Fig. S7).
Pain-related signals occur within the central
nervous system, a process known as central sensitization and also
arise in the periphery due to peripheral inflammation. Peripheral
inflammation is a complex immune process that leads to the release
of inflammatory cytokines in response to injuries, infections, or
chronic conditions, such as cancer, diabetes and stress. These
cytokines enhance peripheral inflammation through the further
release of pain mediators and neurotrophic factors, such as in the
case of nerve growth factor, which releases BDNF from DRG neurons,
thus further enhancing the sensitization of nociception and
neuropathic pain (219,220) (Fig.
S7). Most likely, these cytokines trigger epigenetic changes
through a vast network of signaling pathways. For instance, in
animal models of arthritis, colitis and hepatitis, treatment with
HDAC inhibitors, such as phenylbutyrate and trichostatin A,
valproic acid (VPA) and suberyolanilide hydroxamic acid (SAHA or
vorinostat), and ITF2357 has been shown to reduce the expression of
pro-inflammatory cytokines, such as IL-1β and TNF-α (221-224).
These cytokines cause the hyperacetylation of H4 histones at
pro-inflammatory promoters, such as the granulocyte-macrophage
colony-stimulating factor (GM-CSF), through the action of the
transcription factor NF-κB and its subunits p50 and p65 (225,226); this enhanced inflammation is
perhaps responsible for the enhanced expression of TRP channels
(Fig. S7). HDAC inhibitors also
exert analgesic effects in inflammatory pain via mGluR2 receptors
in both the DRG and spinal cord (227). The mGluR2 receptor gene is
upregulated by increased acetylation of p65/RelA on lysine
310(227). Another example of
histone modifications is the methylation of H3K4 via
methyltransferase SET7/9, which recruits NF-κB to pro-inflammatory
genes (228). Thus, the cytokine
activation stimulates downstream signaling pathways that activate
NF-κB through histone modifications that alter nuclear gene
expression. NF-κB plays a critical role in the downstream
regulation of TRP channels. It can directly bind to the promoter
regions of TRP genes, and this notable activation of TRP channels
can lead to ionic changes both inside and outside the cell, and
their interactions, e.g., ankyrin repeat domain binding to the
cytoskeleton, ultimately triggering a cascade of downstream
signaling pathways. TRP channels affect multiple signaling
pathways, including the MAPK pathway, the TGF-β signaling pathway,
the NF-κB pathway and the AMPK pathway (186), as aforementioned.
The activation of TRPA1 has been observed in M1
macrophages in mice. TRPA1 regulates H3K27me3 modification by the
EZH2 subunit of the PRC2 complex by protecting it from degradation
via the proteasome pathway to inhibit M1 macrophage activation
(229). TRPA1 deficiency leads to
EZH2 degradation and chromatin opening, promoting M1
macrophage-associated gene transcription and atherosclerotic plaque
formation (230). Hence TRPA1
reduces atherosclerosis plaque formation in third-order branches of
the superior aorta of patients and mice (230). However, the precise mechanism and
the specific PRC2 subunit(s) involved remain unclear, and
high-resolution structural confirmation is lacking. In addition to
its interaction with PRC2, TRPA1 also links calcium signaling to
epigenetic control. Inhibition of TRPA1 reduces CA2+
influx, suppressing CaMKII activity, which in turn alters the
nuclear localization of HDAC4 (Fig.
S7). This disruption prevents MEF2A from binding to DNA,
promoting hypertrophic gene expression and contributing to cardiac
dysfunction (231). Overall, pain
sensitization under conditions of stress involves complex
epigenetic mechanisms regulating TRP channel activity, inflammatory
receptor expression and downstream signaling pathways. These
pathways provide promising therapeutic targets but require further
investigation, particularly in well-controlled in vitro
systems such as isolated L6-S2 DRGs.
Epigenetic regulation through DNA
methylation
There is a well-established link between increased
CpG methylation, MeCP2 binding and aberrant gene expression in
inflammatory pain conditions. For instance, in intervertebral disc
degeneration, chronic pain is associated with increased methylation
at the SPARC gene promoter in both mice and humans (232). Similarly, methylation of the
promoter of the endothelin-1 B receptor (ET_B) has been
observed in biopsies from painful human oral cancers, but not in
non-painful oral dysplasia. The restoration of ET_B receptor
expression has been found to reduce oral pain (233). Perhaps SPARC and
ET_B expression is linked directly or indirectly to TRP
channels.
One of the most compelling examples of the role of
DNA methylation in pain regulation involves the TRPA1 gene.
Increased TRPA1 promoter activity has been associated with a lack
of DNA methylation during states of high pain threshold. In a
previous study, the researchers employed methylated DNA
immunoprecipitation and deep sequencing on peripheral blood
leukocytes from 50 identical twins and 50 unrelated individuals to
assess responses to high or low heat pain sensitivity. They
identified the TRPA1 promoter as a key site influencing both
thermal and mechanical pain sensitivity (234). In the same study analyzing DNA
from whole-blood samples of 75 healthy volunteers, a specific CpG
site within the TRPA1 promoter was found to be hypermethylated in
individuals with a low threshold for pressure-induced pain.
Moreover, notable sex-based differences were observed: Females
exhibited higher methylation levels at this site and exhibited
greater sensitivity to pressure pain compared to males (234).
Epigenetic regulation through
miRNAs
Epigenetic regulation by miRNAs plays crucial roles
as housekeeping and regulatory elements in key biological
processes, such as early development, cell proliferation, fat
metabolism, differentiation and apoptosis (235). As they regulate over one-third of
human genes, miRNAs are implicated in numerous medical conditions,
including cardiovascular, cerebrovascular and neurodegenerative
disorders. Increasing evidence suggests their involvement in pain
modulation, both nociceptive and neuropathic pain models. In
several rodent models of pain, such as spinal nerve ligation,
spared nerve injury, CFA-induced inflammatory pain and
chemotherapy-induced pain (e.g., histone deacetylase inhibitor
JNJ-26481585 model), significant changes in miRNA expression
profiles have been reported (236). These miRNAs are secreted by immune
and non-immune cells during neuroinflammation caused by peripheral
nerve injury and function through known pro-inflammatory signaling
pathways, including IRAK/TRAF6, TLR4/NF-κB, CXCR4, TXNIP/NLRP3
inflammasome, MAPK, TNF-α and TLR5 (182,237).
Several specific miRNAs contribute to the
activation or inhibition of these signaling cascades. For example,
miR-590-3p is involved in inflammation in diabetic neuropathic pain
(238), while miR-214-3p is
downregulated in spinal astrocytes following spinal nerve ligation
(239). MiR-146a-5p inhibits NF-κB
activation (240,241), and miR-381 suppresses HMGB1
expression (Table II) (242,243). miR-362-3p downregulates BAMBI, and
the inhibition of miR-155 or miR-221 alleviates neuropathic pain by
enhancing SOCS1 expression via NF-κB and p38-MAPK inhibition
(Table II) (182,244-247).
In CFA-induced inflammatory pain, blocking miR-22 reduces
mechanical allodynia and thermal hyperalgesia (248). Additionally, miR-183 suppresses
the expression of pro-inflammatory cytokines (IL-6, IL-1β and
TNF-α) and the expression of ion channels, such as TRPV1,
Nav1.3, Nav1.7 and Nav1.8 in DRG neurons to
reduce osteoarthritic pain (132)
(Figs. S4, S7, and Table
II).
Additional miRNAs, including miR-28-5p, miR-128-3p,
miR-136, miR-150, miR-200b and miR-429 modulate neuroinflammation
and neuropathic pain progression by inhibiting zinc finger
E-box-binding homoeobox 1 expression (Table II) (249-252).
miR-23a reduces hyperalgesia via CXCR4 and the TXNIP/NLRP3
inflammasome in spinal glial cells (253). Moreover, miR-140 and miR-144
alleviate hyperalgesia and decrease the secretion of inflammatory
mediators by targeting sphingosine-1-phosphate receptor 1 and RAS
p21 protein activator 1, respectively (254,255). Furthermore, miR-216a-5p inhibits
Wnt/β-catenin signaling by targeting KDM3A, reinforcing the
regulatory potential of miRNAs in chronic pain (Table II) (256).
Chemotherapy-induced peripheral neuropathy is a
frequent and debilitating side-effect associated with the use of
agents, such as OXL and bortezomib (BTZ), and it has been linked to
miRNA dysregulation via the oxidative stress-TRPA1 signaling axis.
OXL, a third-generation platinum-based chemotherapeutic used in
metastatic gastrointestinal cancers, has been shown to increase
miR-155 levels, thereby activating the oxidative stress-TRPA1
pathway (257). This results in
mechanical allodynia and cold hyperalgesia. The intrathecal
administration of miR-155 inhibitors in OXL-treated rats has been
shown to restore impaired Nrf2-ARE signaling in the dorsal horn of
the spinal cord, reduce the expression of NADPH oxidase subtype 4,
and decreased oxidative stress markers, such as 8-iso PGF2α and
8-OHdG (257). Conversely, the
OXL-induced downregulation of miR-141-5p leads to an increased
expression of TRPA1. The intrathecal injection of miR-141-5p
reduces TRPA1 levels and attenuates peripheral pain (258) (Fig.
S7, Table II). Similarly,
miR-155 has been implicated in BTZ-induced neuropathic pain. Its
inhibition leads to the reduced expression of TNFR1, p38-MAPK, JNK
and TRPA1, contributing to analgesic effects (247,259).
Extracellular miRNAs also contribute to pain
signaling. For instance, miRNA let-7b activates nociceptive neurons
through TLR7-TRPA1 coupling, inducing rapid inward currents and
action potentials in DRG neurons (Table II) (247). This effect is dependent on the
presence of both TLR7 and TRPA1, as well as the 5'-GUU GUG U-3'
motif in miRNA let-7b (260,261) (Fig.
S7). Several other miRNAs, including miR-143, miR-21, miR-103,
miR-7a, miR-133a, miR-134 and miR-20a/b, as well as the Kcna2
antisense long non-coding RNA, have been reported to modulate
nociceptor activity in DRG neurons and contribute to pain
processing (Table II) (145,262-266).
In addition, hyper-methylated
m6A-modified mRNAs of TRP channels were identified by
m6A epitranscriptomic microarray analysis in middle ear
cholesteatoma tissues (267). KEGG
pathway analysis revealed that these hypermethylated transcripts
were involved in 26 signaling pathways, including inflammatory
mediator regulation of TRP channels (267). Of note, there appears to be
bidirectional communication between lncRNAs, such as HOX transcript
antisense intergenic RNA (HOTAIR) and TRP channels, mediated via
METTL3-dependent m6A modifications (268). For instance, in glioblastoma, the
upregulation of melastatin-TRPM7 is associated with an increased
expression of lncRNA HOTAIR through calcium influx and subsequent
NF-κB activation. The increased expression of lncRNA HOTAIR has
been linked to a reduced expression of miR-301-3P and a subsequent
decrease in FOSL1 expression, promoting tumorigenesis (269).
Although the dynamic expression of various lncRNAs,
including rhabdomyosarcoma 2 associated transcript, TCL1 upstream
neural differentiation-associated RNA, BDNF-antisense (AS),
metastasis-associated lung adenocarcinoma transcript 1 (Malat1),
Gomafu, KCNA2-AS and HOTAIR has been well characterized in CNS
development, synaptic plasticity, neurodegenerative diseases and
cancer (270), their roles in
regulating ion channels involved in nociceptive or neuropathic pain
remains largely unexplored. For example, the circular RNA
hsa_circ_0023305 was found to significantly enhance TRPM7
expression by functioning as a miR-218-5p sponge, thereby promoting
proliferation and metastasis of laryngeal squamous cell carcinoma
cells (271). Collectively, these
findings underscore the central roles of ncRNAs, including miRNAs,
lncRNAs, and circRNAs, in the regulation of TRP channels and their
potential involvement in both nociceptive and neuropathic pain
states. The continued investigation of miRNA and lncRNA regulatory
networks may provide novel therapeutic avenues for the development
of targeted, non-opioid analgesics aimed at improving outcomes for
patients suffering from chronic pain.
16. Pharmacology of pain highways
Since ion channels control the major flow of ions
across the plasma membrane of neurons that generate and propagate
action potentials, learning about the epigenetic mechanisms that
transform sensory afferent pathways would lead to a large
breakthrough for all types of pain. From the aforementioned
studies, a growing evidence indicates that aberrant changes in DNA
methylation, RNA modification complexes, RNA interference and
histone modifications affecting ion channels can reshape pain
sensitivity trajectories following physical, peripheral, or
visceral injury, central or peripheral nervous system lesions, as
well as neuropathic or chemotherapy-induced pain. While current
treatments rely on analgesics, anticonvulsants and antidepressants,
epigenetic-based interventions hold potential to restore or modify
normal gene expression, protein function and analgesic
responsiveness.
Dysregulated ion channel expression is a hallmark
of nociceptive and neuropathic pain, altering neuronal
excitability. Identifying critical ion channel targets is therefore
essential for developing improved pain therapeutics. For example,
Nav1.7, Nav1.8, and Nav1.9 play critical roles in inflammatory pain
and research on human inherited disorders of nociception has
revealed that Nav1.7 is essential for physiological pain
perception, with point mutations leading to chronic pain syndromes
(272). Sensitivity to TTX is
useful in classifying sodium channel subtypes and distinguishing
their functions across regions, such as the CNS, DRGs and dorsal
horn, as well as their specific activation during nociception.
Peripheral neuronal research has suggested that Nav1.8 interacts
more slowly with carbamazepine in DRG neurons compared to
TTX-sensitive channels (273). The
µO-conotoxin MrVIb (31-amino acid peptide from the venom of the
marine snail, Conus marmoreus) selectively blocks Nav1.8
currents and produces substantial analgesia, indicating that
Nav1.8-selective antagonists may offer superior therapeutic
profiles compared to nonselective VGSC inhibitors (274,275). Additionally, peptide toxins from
tarantulas and marine cone snails represent promising sources of
novel sodium channel inhibitors (276).
REST, also known as NRSF, is a master
transcriptional regulator of neuron-specific genes. It functions
not only during neurogenesis and neuronal differentiation, but also
in mature neurons, particularly during the critical period of
postnatal brain development, where it fine-tunes the expression of
genes involved in synaptic plasticity (277). REST provides neuroprotective
advantage by repressing oxidative stress and β-amyloid toxicity
genes in normal aging (277). From
its broad regulatory role (123),
REST/NRSF has been found as a potential pain therapeutic target; in
several pain models, the direct inhibition of its activity has been
shown to alleviate pain symptoms.
Biological data have elucidated the mechanism of
NRSF binding to NRSE in target genomic sequences, recruiting a
network of other proteins, and how they individually or
collectively contribute to chronic or neuropathic pain.
Specifically, REST recruits histone deacetylase mSin3 at its
N-terminal domain and the major corepressor CoREST at its
C-terminal domain (122) (Figs. S4 and S5). CoREST, in turn, recruits the histone
demethylase LSD1, further reinforcing transcriptional repression.
In addition, NRSF can indirectly recruit the histone
methyltransferase G9a via the chromodomain-containing protein CDYL
(chromodomain Y-like), which bridges REST to histone methylation
activity (122).
Following nerve injury, NRSF upregulation leads to
the transcriptional repression of ion channels and reduced
analgesia that underlie chronic or neuropathic pain. For example,
the upregulation of NRSF downregulates SCN7A (also known as
Nav2.1), which is an atypical VGSC, since it is regulated by a
higher concentration of sodium rather than voltage (278) and the potassium voltage-gated
channel subfamily D member 3 (Kv4.3) in DRG neurons after injury,
thereby lowering the firing threshold and enhancing pain signaling
(122). NRSF also suppresses the
expression of the µ-opioid receptor (MOR), resulting in a loss of
analgesic efficacy, as shown in the injury-induced repression of
Nav1.8 and MOR genes in damaged C-fibers (279,280). In parallel, G9a (histone
methyltranferase, also known as EHMT2) also contributes to
long-term pain sensitization by promoting histone methylation and
subsequently downregulation of potassium channel genes (281).
The pharmacological targeting of NRSF and its
corepressors has revealed promising strategies for alleviating
neuropathic pain. As previously demonstrated, two small-molecule
mimetics, mS-11 and C737 (mimics the helical structure of REST),
which competitively bind to the N-terminal domain of NRSF and
disrupt its interaction with mSin3, attenuate REST-mediated
repression of gene expression. For instance, in a mouse model of
sciatic nerve injury, the administration of mS-11 restored C-fiber
pain thresholds to basal levels (282). Similarly, a small quinolone-like
compound, C91, was shown to inhibit the NRSF-mSin3b interaction
(283), further supporting the
therapeutic potential of targeting this pathway.
HDAC inhibitors prevent the removal of acetyl
groups from histone and non-histone proteins, leading to increased
histone acetylation and a more relaxed chromatin structure that
facilitates gene transcription (284). HDAC inhibitors, such as TSA, (VPA
and SAHA, restore the expression of Nav1.8, thereby recovering
C-fiber-mediated sensory function and alleviating hypoesthesia
(285). Moreover, treatment with
HDAC inhibitors, including TSA and VPA, restores morphine
analgesia, which is associated with an elevated expression of MOR
(14,286). In addition, DNMT3a expression is
upregulated in the DRG and spinal cord of rats with neuropathic
pain, whereas treatment with the isoform-nonspecific DNMT inhibitor
N-phthalyl-L-tryptophan (RG108) enhances MOR expression and
attenuates thermal hyperalgesia in chronic constriction injury
(CCI) models (287).
miRNAs can also be used to target
nociceptive signaling pathways of ion channels
miRNAs, such as miR-96 and miR-384-5p have been
known to decrease the expression of Scn3A
(Nav1.3) (126,127) and alleviate neuropathic pain.
Additional miNAs involved in DRG nociceptive signaling include
miR-182, miR-30b, miR-18, miR-7a, miR-137, miR-183-5p and the
miR-17-92 cluster. The ncRNAs, such as miR-124 and miR-219 (via
MeCP2/CAMKs), miR-103 and miR-32-5p downregulate
Cav1.2, and
Cav3.2 expression, respectively, thereby
attenuating nociceptive signaling. Collectively, these findings
highlight how the epigenetic and post-transcriptional modulation of
ion channel function provides a foundation for next-generation pain
therapeutics.
17. Conclusion and future directions
The majority of ion channels in the spinal cord
play critical roles in nociception. These channels include
voltage-gated sodium (Na+), potassium (K+),
calcium (Ca²+) and TRP channels. They are typically
classified based on their structural features (such as α- and
β-subunits), electrophysiological characteristics (e.g., activation
and inactivation kinetics), and pharmacological sensitivity to
specific modulators or blockers. However, the epigenetic regulation
of these ion channels remains underexplored and warrants more
in-depth investigations for the development of more effective pain
therapies.
These ion channels function in concert to
discriminate between noxious and innocuous stimuli and to modulate
nociceptive signals. This complex, multilevel ‘orchestra’ of ion
channel regulation and activity spans from primary nociceptive
afferents and DRGs to DHNs, spinal interneurons, and projection
neurons of Rexed laminae, transmitting pain signals via the
anterolateral system, notably the spinothalamic tract to the
supraspinal centers. The final destination for the conscious
perception of pain is the somatosensory cortex, specifically the
postcentral gyrus of the parietal lobe, where the spatial, temporal
and intensity features of pain are interpreted. Disruption at any
point in this integrated signaling cascade, whether through ion
channel dysfunction, epigenetic dysregulation, or synaptic
plasticity, can lead to aberrant pain processing and the
development of chronic pain syndromes.
The DRGs and dorsal horn are the major afferent
nociceptive centers. Within the spinal cord, different spinal
segments that correspond to specific body regions have specialized
functions, reflecting their diverse neuronal populations and
varying role in nociception (20).
The Rexed laminae, defined by distinct cytoarchitecture, process
different types of sensory stimuli; laminae I to VI are the
principal nociceptive layers, containing interneurons, projection
neurons, and wide dynamic range neurons distributed across these
laminae (29,30). The spinal cord anatomy changes along
its rostrocaudal axis. At lower spinal levels (e.g., lumbar and
sacral), the ratio of gray matter to white matter is higher due to
fewer ascending and descending fiber tracts. By contrast, at
cervical levels, the white matter proportion increases as ascending
tracts accumulate fibers from lower segments while descending
tracts gradually lose fibers (20).
This structural variation suggests that the epigenetic landscape,
including chromatin accessibility, DNA methylation and histone
modifications, may differ across spinal segments and between spinal
nerves emerging at different vertebral levels. Such
segment-specific epigenetic regulation could influence the local
expression of ion channels, receptors, pain-related genes and their
pathways, thereby shaping regional sensitivity to injury, patterns
of pain sensitization and the development of chronic pain.
Emerging evidence indicates that histone
modifications critically regulate nociceptive ion channels. For
example, H4 acetylation of SCN8A (Nav1.6)
promoter enhances its transcription by promoting the recruitment of
phosphorylated STAT3 and its coactivator p300 and TNF-α cytokine
during inflammation uses the same pathway for SCN8A
expression (Fig. S4) (125). Similarly, in animal models of
arthritis, colitis and hepatitis, HDAC inhibitors reduce the
expression of pro-inflammatory cytokines such as IL-1β and TNF-α
(221-224),
which otherwise induce hyperacetylation of H4 at promoters such as
GM-CSF via NF-κB and its subunits p50 and p65, which increases TRP
channel expression (Fig. S7)
(225,226). Conversely, NRSF downregulates the
Scn10a gene (Nav1.8) and the MOP receptor (Oprm1) in
DRGs by recruiting HDACs, mSin3, and CoREST in neuropathic pain
models (124). NRSF and its
corepressors also repress Kv and K2P channel
genes in OXL-treated mice, while NRSF knockdown in DRGs, mitigates
this repression and alleviates mechanical and cold hypersensitivity
(141). Moreover,
calcium-dependent enzymes, such as HDAC4, CaMKII and
calcineurin respond to intracellular Ca2+ fluctuations
to modulate chromatin structure, DNA methylation and transcription
factor activity (161,162). In turn, epigenetic modifications,
including histone marks and DNA methylation, regulate the
expression of key genes involved in calcium homeostasis and signal
transduction, such as VDCCs, pumps and buffering proteins,
establishing a reciprocal regulatory loop (163). TRP channels exhibit a similar
bidirectional interaction. Both VDCCs and TRPs are targets and
activators of signaling pathways, including MAPK, TGF-β, NF-κB and
AMPK. Thus, the dual role of calcium and TRP channels, as both
modulators and effectors of epigenetic and signaling networks,
render them promising therapeutic targets for chronic pain. The
more in-depth exploration of this bidirectional interplay could
uncover novel nociceptive pathways and guide future
interventions.
DNA methylation plays a pivotal role in regulating
TRP channel expression in peripheral and visceral pain sensitivity.
For instance, the knockdown of DNMT1 and the histone
acetyltransferase EP300 reverses TRPV1 expression by
downregulating the endocannabinoid receptor CNR1 in L6-S2 DRGs,
thereby attenuating visceral hypersensitivity (218) (Fig.
S7). Similarly, increased TRPA1 promoter activity is associated
with reduced DNA methylation during states of high pain threshold
(234).
In addition to DNA methylation, miRNAs secreted by
immune and non-immune cells during neuroinflammation modulate
nociceptive pathways by targeting ion channels and related
signaling molecules. These miRNAs function through established
pro-inflammatory pathways, including IRAK/TRAF6, TLR4/NF-κB, CXCR4,
TXNIP/NLRP3 inflammasome, MAPK, TNF-α, and TLR5 (182,237), thereby influencing the activation,
transmission, and sensitization patterns of nociceptive circuits.
Specific miRNAs, such as miR-30b downregulate Scn3a,
Scn8a, and Scn9a (129-131),
while miR-183 suppresses Scn3a, Scn9a, Scn10a,
and TRPV1 expression in DRG neurons (132), alleviating neuropathic pain in
models such as SNL or OXL-induced neuropathy. Likewise, miR-103,
miR-32-5p, miR-125, and miR-219 have been shown to either
upregulate or downregulate the expression of VDCCs (179,180), while miR-146a-5p, miR-381,
miR362-3p, miR155, miR-183 regulate TRP channels, highlighting
miRNAs as promising nociceptive targets (132,182,244-246).
Future studies are required to employ
high-throughput miRNA profiling, digital PCR and quantitative PCR
to assess miRNA expression patterns. Additionally, chromatin
immunoprecipitation sequencing (ChIP-seq), ChIP-chip, ATAC-seq and
bisulfite sequencing will be invaluable for characterizing histone
modifications and DNA methylation landscapes in DRG and DHNs across
different spinal segments. Together, these integrated approaches
will advance our understanding of epigenetic regulation in pain
pathways and help identify novel therapeutic targets for the
management of chronic pain.
Supplementary Material
Anatomy and organization of the human
spinal cord. (A) Dorsal view illustrating the eight cervical, 12
thoracic, five lumbar, five sacral, and one coccygeal region with
key landmarks: Cervical and lumbar enlargements, pyramidal
decussation and filum terminale. (B) Spinal segmentation diagram
highlighting spinal cord regions, spinal nerves, the conus
medullaris (orange), and cauda equina (purple). (C) Cross-section
illustrating the central canal, dorsal root ganglion, roots, rami,
pia mater, arachnoid mater, dura mater, and dentate ligament
anchoring the cord. The figure was adapted from the studies by
Byrne [Byrne JHe: Neuroscience Online: An Electronic Textbook for
the Neurosciences. Department of Neurobiology and Anatomy, McGovern
Medical School at The University of Texas Health Science Center at
Houston (UTHealth), 1997] and Tan et al [Tan S, Faull RLM
and Curtis MA: The tracts, cytoarchitecture, and neurochemistry of
the spinal cord. Anat Rec (Hoboken) 306: 777-819, 2023] after
obtaining relevant permission.
Schematic representation of Rexed
laminae and major nuclei within the spinal cord gray matter.
Color-coded regions represent functional subdivisions, as follows:
Purple, sensory processing (dorsal horn, laminae I-VI); green,
visceral/autonomic function (intermediolateral cell column); red,
motor function (ventral horn, laminae VIII-IX); gray, commissural
neurons and glia around the central canal (lamina X). The
information presented in this figure and the figure itself was
adapted from the study by Byrne [Byrne JHe: Neuroscience Online: An
Electronic Textbook for the Neurosciences. Department of
Neurobiology and Anatomy, McGovern Medical School at The University
of Texas Health Science Center at Houston (UTHealth), 1997] after
obtaining relevant permission.
Nociceptive pathways in the spinal
cord. Schematic representation of nociceptive signaling from
peripheral sensory neurons to the cerebral cortex. First-order
neurons, with cell bodies located in the DRGs, relay afferent
signals through the dorsal roots into the spinal cord, where they
synapse with the second-order interneurons and projection neurons
in the dorsal horn. These neurons decussate and ascend via the
anterolateral system, including the lateral and anterior
spinothalamic tracts and the SRT, to the brainstem nuclei (LPB,
CVLM, PAG) and the thalamic nuclei (VPL, VPM). In the thalamus,
third-order neurons project to the postcentral gyrus of the
parietal lobe, where nociceptive information is perceived.
Descending modulation occurs via corticospinal and extrapyramidal
tracts, originating in the cortex and brainstem, which regulate
nociceptive input at the spinal level. SRT, spinoreticular tract;
LPB, lateral parabrachial nucleus; CVLM, caudal ventrolateral
medulla; PAG, periaqueductal gray; VPL, ventral posterolateral;
VPM, ventral posteromedial; DRG, dorsal root ganglion.
Epigenetic regulation of sodium
channel isoforms in DRG nociceptors. Epigenetic activation of
Scn8a (Nav1.6) by the increased acetylation of histone H4 at
the Scn8a gene promoter, which recruits phosphorylated STAT3
and its coactivator p300 in DRGs induced by proinflammatory
cytokine TNF-α (Ding HH, Zhang SB, Lv YY, Ma C, Liu M, Zhang KB,
Ruan XC, Wei JY, Xin WJ and Wu SL: TNF-α/STAT3 pathway
epigenetically upregulates Nav1.6 expression in DRG and contributes
to neuropathic pain induced by L5-VRT. J Neuroinflammation 16: 29,
2019). Epigenetic repression of Scn10a (Nav1.8) and MOP by
REST/NRSF in DRG neurons during neuropathic pain. The NRSF
repression complex contains HDAC1, SAP30, SAP18 and other proteins
(Su XJ, Shen BD, Wang K, Song QX, Yang X, Wu DS, Shen HX and Zhu C:
Roles of the neuron-restrictive silencer factor in the
pathophysiological process of the central nervous system. Front
Cell Dev Biol 10: 834620, 2022). Various miRNAs (miR-30b, miR-96,
miR-182, miR-183 and miR-384-5p) downregulate sodium channel
expression: miR-30b suppresses Scn3a, Scn8a, and
Scn9a; miR-96 downregulates Scn3a (Nav1.3);
miR-384-5p targets Nav1.3; miR-182 reduces Scn9a (Nav1.7);
and miR-183 inhibits Scn3a, Scn9a, and Scn10a.
The REST/NRSF complex of this figure was adapted from Su et
al., 2022 (Su XJ, Shen BD, Wang K, Song QX, Yang X, Wu DS, Shen
HX and Zhu C: Roles of the neuron-restrictive silencer factor in
the pathophysiological process of the central nervous system. Front
Cell Dev Biol 10: 834620, 2022). This diagram was created using
BioRender. DRG, dorsal root ganglion; MOP, μ-opioid
receptor; NRSF/REST, neuron-restrictive silencer factor or
repressor element-1 (RE1)-silencing transcription factor;
miRNA/miR, microRNA.
Epigenetic modifications of K
channels. Schematic representation of a DRG neuron highlighting key
potassium channel isoforms: Voltage-gated (Kv),
calcium-activated (KCa), inward rectifier
(Kir) and tandem or two-pore domain (K2P).
Inside the nucleus of DRGs and DHN, OXL treatment represses
Kv and K2P via NRSF. The N-terminal domain of
NRSF binds HDACs and represses target genes while the C-terminal
domain binds to CoRESTs and further interacts with HDAC1, HDAC2 and
MeCP2 to promote and maintain methylated CPG-dependent gene
silencing (Su XJ, Shen BD, Wang K, Song QX, Yang X, Wu DS, Shen HX
and Zhu C: Roles of the neuron-restrictive silencer factor in the
pathophysiological process of the central nervous system. Front
Cell Dev Biol 10: 834620, 2022). miRNAs such as miR-183-5p, miR-137
and the miR-17-92 cluster downregulate K+ channel
expression, ultimately impact nociceptive pathways. The REST/NRSF
complex of this figure was adapted from the study by Su et
al (Su XJ, Shen BD, Wang K, Song QX, Yang X, Wu DS, Shen HX and
Zhu C: Roles of the neuron-restrictive silencer factor in the
pathophysiological process of the central nervous system. Front
Cell Dev Biol 10: 834620, 2022). This diagram was created using
BioRender. DRG, dorsal root ganglion; NRSF/REST, neuron-restrictive
silencer factor or repressor element-1 (RE1)-silencing
transcription factor; miRNA/miR, microRNA; CoRESTs, REST
corepressor proteins; DHN, dorsal horn neuron; OXL, oxaliplatin;
HDAC, histone deacetylase; MeCP2, methyl-CpG binding protein
2.
Epigenetic regulation of VGCCs in DRG
neurons. Highlighting six classes of Ca2+ channels: L
(Cav1.1- Cav1.4), N (Cav2.1), P/Q
(Cav2.2), R (Cav2.3), and T
(Cav3.1-Cav3.3). Calcium ions
(Ca2+) activating the MAPK/JNK pathway, leading to
phosphorylation of histone H3 under peripheral inflammation is
shown. In chronic nerve injury model, hypomethylation of the
CACNA1C promoter increases Cav1.2 expression and
enhances Ca2+ influx in sensory neurons. HDAC inhibitors
suppress the expression of N-type VGCCs (Cav2.1) and
reduce nociceptive hypersensitivity in rodent models.
Ca2+ influx through L-type VGCCs promotes enhancer RNA
(eRNA) synthesis via increased H3K4me1 levels and CBP
recruitment. Ca2+ also activates CaMKII, which
phosphorylates MeCP2, causing its release from the BDNF promoter
and inducing BDNF transcription. This is associated with reduced
H3K9 methylation, increased acetylation at the same site, and lower
CpG methylation frequency. miRNAs such as miR-124 and miR-219 via
MeCP2/CAMKs; miR-103 and miR-32-5p, downregulate
Cav1.2, Cav3.2
expression respectively, thereby attenuating nociceptive signaling.
This figure was created using BioRender. VGCCs, voltage-gated
calcium channels; DRG, dorsal root ganglion; HDAC, histone
deacetylase; CBP, CREB-binding protein; CaMKII,
Ca2+/calmodulin-dependent protein kinase II; BDNF,
brain-derived neurotrophic factor; MeCP2, methyl-CpG binding
protein 2; miRNA/miR, microRNA; DNMT, DNA methyltransferase; TET,
ten-eleven translocation methylcytosine dioxygenase.
Epigenetic regulation of nociception
through peripheral inflammation-induced TRP channel expression in
DRG neurons. Peripheral inflammation triggers pro-inflammatory
cytokines that induce histone, DNA methylation and miRNA changes,
regulating TRP channel expression and nociception. For example,
reduced DNA methylation increases TRPA1 promoter activity during
states of high pain threshold, while chronic stress downregulates
CNR1 and upregulates TRPV1. HAT EP300 and DNMT1 enhance TRPV1
expression and visceral sensitivity in L6-S2 DRGs. HDAC inhibitors
lower IL-1β and TNF-α levels, decrease H4 hyperacetylation, and
suppress TRP expression via NF-κB. HDACis also exert analgesic
effects via mGluR2 in DRG and spinal cord. SET7/9
methyltransferase-mediated H3K4 methylation recruits NF-κB to
pro-inflammatory genes. Inhibiting TRPA1 reduces Ca2+
influx and CaMKII activity, altering HDAC4 localization and MEF2A
DNA binding. miRNAs (e.g., miR-143, miR-21, miR-103, miR-7a,
miR-133a, miR-134 and miR-20a/b) target TRP channels, while miR-183
suppresses pro-inflammatory cytokines and ion channels like TRPV1
and Nav1.7, and Nav1.8 in DRG neurons. This
figure was created using BioRender. DRG, dorsal root ganglion; TRP
channel, transient receptor potential channel; HDAC, histone
deacetylase; DNMT, DNA methyltransferase; miRNA/miR, microRNA;
CaMKII, Ca2+/calmodulin-dependent protein kinase II;
MEF2A, myocyte enhancer factor 2A.
Acknowledgements
The author is deeply grateful to Dr Ramesh
Raghupathi, Professor at the Department of Neurobiology and Anatomy
at Drexel University College of Medicine (Philadelphia, PA, USA),
for his inspiration with the writing of the present review. The
author would also like to thank Dr Vijay Juneja, Lead Scientist at
the Eastern Regional Research Center (ERRC), Wyndmoor, Pennsylvania
for his invaluable assistance with the editing of the present
review.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Author's contributions
The author KKA wrote and edited the manuscript. The
author has read and approved the final manuscript. Data
authentication is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The author declares that there are no competing
interests.
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