TRPV1‑mediated central sensitisation: Core mechanisms of migraine chronification and novel targeted therapeutic strategies (Review)

Introduction

Migraines are a leading cause of disability among neurological disorders worldwide. They are characterized by recurrent episodes of moderate to severe throbbing headaches, often accompanied by photophobia, phonophobia and nausea. Severe cases may also result in disability (1). The global prevalence of migraine is continuing to rise (2) and although the burden remains markedly higher in women compared with men, the rate of increase is faster among male patients. Notably, prevalence among adolescents is also increasing rapidly (2,3).

The pathogenesis of a migraine remains incompletely understood. Previous research (4,5) has implicated abnormalities in neurovascular regulation, genetic factors, endocrine disorders, environmental triggers and psychophysiological factors. For example, in polycystic ovary syndrome, an imbalance in the neuropeptide regulatory network has been reported to contribute towards central-peripheral neuroendocrine dysfunction (6). However, growing evidence indicates that central sensitisation is the core pathophysiological basis for recurrent and chronic migraines (7,8). Central sensitization refers to a persistent, plastic increase in the reactivity of neurons in the central nervous system (CNS) pain pathways. Clinically, it manifests as a lowered pain threshold (hyperalgesia), pain responses to non-noxious stimuli (allodynia) and expansion of pain distribution, all key contributors to characteristic migraine symptoms such as hyperalgesia and touch-induced pain (9-11). Recent studies have further demonstrated that persistent inflammatory stress driven by cellular senescence can exacerbate abnormal CNS plasticity. Although this mechanism has been primarily described in neurodegenerative diseases such as Alzheimer's disease, it offers a new perspective for understanding the long-term maintenance of central sensitisation in migraines (12).

The transient receptor potential (TRP) channel family comprises non-selective cation channels widely distributed on mammalian cell surfaces. These channels have been implicated in a number of physiological processes, including temperature sensing, mechanotransduction and chemical signal transduction (13,14). TRPV1, also known as the capsaicin receptor, belongs to the TRPV subfamily and can be activated by numerous stimuli, including capsaicin, temperatures >43°C and acidic environments (pH <5.9). TRPV1 serves a key role in pain signal transmission (15,16). In the pathophysiology of a migraine, inflammatory factors released from the meninges, such as calcitonin gene-related peptide (CGRP), nitric oxide (NO) and prostaglandins, along with local tissue acidification, markedly activate and sensitize TRPV1 on trigeminal ganglion (TG) neurons, initiating pain signal transmission to the CNS (17). Membrane functional proteins and ion channels can serve as key biomarkers for disease prognosis and targeted intervention, offering notable references for precision therapeutic screening (18).

Previous studies have reported the presence of TRPV1 expression in key CNS regions involved in nociceptive processing, including the trigeminal nucleus caudalis (TNC), thalamus and periaqueductal grey (PAG) (19,20). At the central level, TRPV1 directly participates in regulating presynaptic neurotransmitter release and postsynaptic neuronal excitability. TRPV1 also influences plasticity changes such as long-term potentiation (LTP) and promotes glial cell activation and the release of pro-inflammatory cytokines. These actions collectively drive the formation and maintenance of central sensitisation (21,22). Therefore, targeting TRPV1 may not only block initial pain afferent transmission but also directly intervene in central sensitisation, offering new preventive and therapeutic strategies for migraine management. Adjunctive measures, such as nutritional interventions and homeostatic regulation, can effectively modulate neuronal excitability and physiological status, providing complementary approaches for the comprehensive management of chronic neuropathic pain (23).

Although previous reviews have explored the role of TRPV1 in pain transmission or the mechanisms of central sensitisation in migraine, the majority of studies have focused solely on peripheral nociceptors. However, a systematic, integrated analysis of the direct involvement of TRPV1 in the development and maintenance of central sensitisation within central pain-processing regions is lacking. Therefore, the present review adopted 'TRPV1-mediated central sensitisation' as a unified theoretical framework to systematically elucidate the molecular mechanisms underlying migraines. The aim was to provide new theoretical foundations and translational insights for research into the pathogenesis of a migraine and its clinical treatment.

Associations between central sensitisation and migraines

Core characteristics of central sensitization

Central sensitisation is a pathological state in which pain transmission pathways of the CNS (primarily including the spinal dorsal horn, trigeminal spinal tract nucleus, thalamus and cerebral cortex) exhibit abnormally heightened excitability following prolonged exposure to painful stimuli. First proposed and demonstrated by Woolf (24) in 1983, it is the core pathological basis for the development of chronic pain. The clinical features of central sensitisation include a lowered pain threshold, hyperalgesia, allodynia and expanded pain distribution, which closely align with the sensory abnormalities observed in migraines, such as scalp tenderness, photophobia and phonophobia (25,26).

Clinical studies have found that the pressure pain threshold in patients with migraines is markedly lower compared with that of healthy individuals. This represents the core quantitative manifestation of central sensitisation (27,28). The degree of pain sensitivity is associated with both the headache attack frequency and the extent of disease chronicity, with a more notable reduction in pain threshold observed in patients with chronic migraines (29,30). The underlying pathophysiological mechanisms involve abnormalities in multi-level pain regulation. The pressure pain threshold indirectly reflects the excitability levels of neurons in the spinal dorsal horn and trigeminal spinal tract nucleus (31,32). Progressive lowering of the pain threshold is associated with N-methyl-D-aspartate (NMDA) receptor-mediated LTP at spinal synapses, as well as weakened function of descending inhibitory pathways in the brainstem (32,33). Standardized reference indices established through quantitative sensory testing, including thermal and mechanical detection thresholds, thermal and mechanical pain thresholds, pressure pain thresholds and pain superposition, can objectively identify pain sensitivity phenotypes in patients with migraines. This provides a reliable basis for clinical differentiation between episodic and chronic migraine and for assessment of central sensitisation (28,34). This also indicates that central sensitisation in migraines is a continuous, dynamic process that progresses from acute to chronic, rather than a series of discrete, stage-based events.

Role of central sensitisation in migraine pathogenesis

Amplification of pain perception

During a migraine attack, the abnormal enhancement of pain perception is a multistage pathophysiological process initiated peripherally and regulated centrally (35). This process begins with the activation of the trigeminal vascular system. Its sensory nerve endings release neuropeptides such as CGRP and substance P (SP), triggering neurogenic inflammation that continuously stimulates peripheral nociceptors (36). The resulting signals are transmitted to the trigeminocervical complex (TCC) in the brainstem (37). There, through sustained activation of the NMDA receptor system, the depolarization threshold of neurons is lowered, making them prone to firing in response to normal or subthreshold stimuli. This leads to enhanced responses and an expanded receptive field, establishing central sensitisation (38).

In addition to local sensitisation, an imbalance in the descending modulatory system connecting the PAG to the rostral ventromedial medulla (RVM) also contributes to central sensitisation. Under physiological conditions, activation of RVM 'OFF cells' projects to the TCC, releasing inhibitory neurotransmitters such as serotonin and norepinephrine to produce analgesia (39-41). However, during recurrent migraine attacks, this balance is disrupted. On the one hand, functional exhaustion of OFF cells or downregulation of inhibitory receptor sensitivity in the TCC leads to weakened descending inhibition (42,43); on the other hand, sensitized TCC abnormally drives excessive activation of RVM 'ON cells', which release excitatory neurotransmitters such as glutamate to the TCC, enhancing its excitability (44,45). The combined effects of weakened descending inhibition and enhanced facilitation amplify pain signals at the central level.

Chronicity and recurrence

Central sensitisation is the core pathological mechanism underlying the transition from an episodic to chronic migraine. Acute attacks originate from activation of the peripheral trigeminal neurovascular system and CGRP release, with nociceptive signals continuously ascending to the TNC (46,47). If attacks recur, this leads to enhanced glutamatergic transmission, excessive NMDA/α-am ino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation and an influx of Ca2+. These changes induce synaptic plastic alterations such as LTP, leading to weakened endogenous inhibition and a lowered central response threshold. Ultimately, this clinically progresses to a chronic migraine, defined as ≥15 headache days per month (48,49). During this process, LTP-like synaptic potentiation occurs in pain network nodes, including the trigeminocerebellar complex, thalamus, anterior cingulate cortex and insula. Abnormal spontaneous discharges further persist between attacks, forming a cycle in which 'attacks exacerbate sensitisation and sensitisation triggers attacks (50).

Development of associated symptoms

There are a number of symptoms that accompany migraines, such as photophobia, phonophobia, nausea, vomiting and cognitive impairment. These may arise from the spread of central sensitisation from nociceptive pathways to adjacent sensory information processing pathways.

Photophobia and phonophobia originate from brainstem-thalamic sensory integration dysfunction. Abnormally excited, hypersensitive TCC ascending pathways cause the thalamus to lose its sensory filtering capacity. Physiological light and sound signals are amplified and cause abnormal activation of emotion-associated brain regions such as the insula and cingulate gyrus (51-53). In addition, blue light hypersensitivity, mediated by intrinsically photosensitive retinal ganglion cells, lowers cortical spreading depression thresholds, activating the thalamic-trigeminovascular pathway, synergistically driving photophobia with central sensitisation (54).

Nausea and vomiting arise from abnormal activation within brainstem viscerovagal-autonomic integration nuclei. The sensitized TNC enhances functional connectivity with the nucleus tractus solitarius and reticular formation through trigeminal-vagal reflexes, lowering the vomiting centre threshold (55-57). Concurrent autonomic dysfunction and vestibular-cross sensitisation abnormally couple headache signals with the vomiting reflex, causing them to occur synchronously (58,59). Furthermore, cognitive and emotional disturbances result from sensitisation spreading to the prefrontal cortex and limbic system, manifesting as fatigue, cognitive fog and mood swings. This indicates that central sensitisation has expanded to functional networks throughout the entire brain (60,61).

Role of TRPV1 in central sensitization

Central sensitisation serves a key role in migraine pathogenesis, as numerous brain regions and signalling pathways are involved. Among these, TRPV1 is a key molecule regulating this process. Persistent injury or inflammation can upregulate the activity and expression of central TRPV1. This subsequently enhances the transmission of central pain signals, lowers the pain threshold and disrupts the excitatory-inhibitory balance, thereby amplifying and spreading pain signals (62,63). In chronic pain, sustained central TRPV1 activation may even induce structural remodelling of neural circuits. This drives central sensitisation from an acute adaptive state, to a self-sustaining pathological state (64,65).

Biological properties of TRPV1

TRPV1 channels are homotetramers or heterotetramers composed of four subunits. Each subunit contains six transmembrane domains (S1-S6), with both N- and C-termini located intracellularly. The pore region between S5 and S6 mediates ion selectivity (66). Functionally, the intracellular N-terminal ankyrin repeat domain participates in channel assembly and sensitisation (for example, ATP binding enhances responsiveness). Meanwhile, key residues in the C-terminal TRP domain (such as I696 and W697) serve as core sites for activation by stimuli (such as capsaicin and heat). Mutations at these sites markedly reduce sensitivity (67).

With regard to tissue distribution, TRPV1 is primarily concentrated in neural tissues involved in pain transmission, with smaller amounts present in non-neural tissues such as the cardiovascular system and skin. In the peripheral nervous system, TRPV1 is highly expressed in afferent pain fibres, such as those in the dorsal root ganglia (DRG) and TG, where it receives and transmits pain signals. In the CNS, it is widely distributed at key nodes of pain pathways, including the spinal dorsal horn, brainstem, thalamus and sensory cortical areas (68). Among these, the TG serves as the origin of afferent pain signals from the head and face, while the spinal dorsal horn acts as the core site for signal integration and regulation of central sensitisation; collectively, these structures are key targets for TRPV1 involvement in migraine pathogenesis (69). Given its specific distribution and regulatory functions in both peripheral and central pain pathways, TRPV1 serves a notable role in the central sensitisation mechanisms of migraine (70,71).

Mechanisms of action regarding TRPV1-mediated central sensitisation in migraines

As a key regulator of central sensitisation, TRPV1 mediates the onset and reversal of central sensitisation through a number of synergistic mechanisms, including regulation of neurotransmitter release, activation of glial cells, the driving of inflammatory responses and modulation of synaptic plasticity.

Regulation of neurotransmitter release and disruption pain transmission homeostasis

Neurotransmitter imbalance is a key factor in the development of central sensitisation. TRPV1 alters the excitatory-inhibitory balance in pain transmission pathways by bidirectionally regulating the release of excitatory neurotransmitters (including CGRP, SP and glutamate) and inhibitory neurotransmitters [such as γ-aminobutyric acid (GABA)].

As a central neurotransmitter in migraine pathogenesis, CGRP release is tightly regulated by TRPV1. During a migraine attack, TRPV1 activation triggers an influx of Ca2+. This results in two effects: It triggers the rapid release of CGRP vesicles and activates the Ca2+/calmodulin-dependent protein kinase (CaMK)/cAMP response element-binding pathway, upregulating CGRP expression (72,73). Released CGRP binds to its receptor, activates protein kinase C (PKC) and feedback-enhances TRPV1 sensitivity, forming a positive feedback loop (74). In addition, CGRP can directly act on type 2 neurons in the trigeminal nerve, inducing the expression of the cellular proto-oncogene Fos and increasing neuronal excitability. It also promotes the polarization of microglia toward the M1 phenotype, leading to the release of inflammatory factors such as IL-1β, IL-6 and TNF-α (75,76). TRPV1 antagonists can notably inhibit CGRP release, thereby blocking this positive feedback loop (77). Furthermore, insulin can promote CGRP release by activating TRPV1, thereby increasing headache susceptibility. This further determines the key regulatory role of TRPV1 in CGRP release (73).

SP release is also regulated by TRPV1, as upon activation of TRPV1, SP is released, which in turn activates the neurokinin-1 receptor, enhancing TRPV1 activity and lowering the channel activation threshold (78,79). SP can also activate glial cells to release inflammatory factors, including TNF-α, IL-1β and IL-6, indirectly promoting central sensitisation (80-82). TRPV1 antagonists inhibit SP release, thereby blocking the initiation of peripheral inflammation and central sensitisation (83,84).

Excessive glutamate release is a direct driver of central sensitisation. TRPV1 activation promotes increased glutamate release in the spinal dorsal horn, TNC and other regions. This glutamate activates postsynaptic AMPA/NMDA/metabotropic glutamate receptors, inducing the formation of LTP. In turn, sensitized TRPV1 further promotes glutamate release, forming a cycle (48,85,86). However, TRPV1 antagonists can reduce postsynaptic neuronal excitability by blocking excessive glutamate release (87,88).

In comparison with the increase in excitatory neurotransmitters, attenuation of GABAergic inhibition represents another key mechanism of central sensitisation. First, TRPV1 activation directly reduces GABA release from inhibitory interneurons. Second, TRPV1 activation can activate kinases such as PKC and protein kinase A (PKA), leading to phosphorylation of GABA-A receptors and downregulation of their membrane expression (89). Furthermore, activated glial cells release TNF-α, inhibit glutamate decarboxylase and promote the reuptake of GABA transporters. This results in the sustained reduction of GABA in the synaptic cleft (90). Notably, GABA itself can inhibit the cAMP/PKA pathway by activating GABA-A receptors and signalling through the inhibitory G protein subtypes Gi/o, thereby causing the dephosphorylation of TRPV1. This constitutes an endogenous negative feedback mechanism (91,92). Following TRPV1 desensitisation or antagonism, GABAergic inhibition is restored (93).

The combined effect of increased release of excitatory neurotransmitters (including CGRP, SP and glutamate) and reduced activity of the inhibitory neurotransmitter (such as GABA) results in a net enhancement of synaptic transmission. This provides the necessary depolarizing basis for the establishment of LTP (Fig. 1A).

Figure 1 Schematic diagram illustrating the mechanism by which TRPV1 mediates central sensitisation in the trigeminal-cervical complex. (A) Presynaptic regulation: Positive feedback (red arrows) and negative feedback (blue arrows) loops involving excitatory (CGRP/SP/Glu) and inhibitory (GABA) neurotransmitter signals. (B) Glial cell activation: M1-type microglia release inflammatory mediators; dysfunction of reactive astrocytes' GLT-1 (red cross). (C) Inflammatory signalling pathways: PGE2 activates EP receptors, promoting cytokine transcription through CaMKII/NF-κB (purple arrows) and MAPK (green arrows) pathways. (D) Postsynaptic plasticity: CaMKII and ERK phosphorylate AMPA and NMDA receptors, respectively, driving LTP (grey area) and central sensitisation. This diagram illustrates how TRPV1 synergistically mediates central sensitisation through numerous pathways involving presynaptic, glial, inflammatory and postsynaptic mechanisms. Arrows of different colours represent specific signal transduction modes. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CGRP, calcitonin gene-related peptide; CGRP-R, CGRP-receptor; EP, prostaglandin E receptor; EP3, prostaglandin E receptor subtype 3; GABA, γ-aminobutyric acid; GLT-1, glutamate transporter 1; Glu, glutamate; GluR1, glutamate receptor 1; LTP, long-term potentiation; NK1-R, neurokinin 1 receptor; NMDA, N-methyl-D-aspartate receptor; NR1, NMDA receptor subunit 1; NR2B, NMDA receptor subunit 2B; PGE2, prostaglandin E2; PKA, protein kinase A; PKC, protein kinase C; SP, substance P; TNC, dorsal subnucleus of the trigeminal-cervical complex; TRPV1, transient receptor potential vanilloid subtype 1.

Activating glial cells to amplify the central sensitisation effect

Glial cell activation is a key step in the onset and progression of central sensitisation and TRPV1 is implicated through both direct and indirect mechanisms.

Microglial activation is an early event in initiating central sensitisation. On the one hand, microglia functionally express TRPV1 on their surface. During a migraine attack, pain signals can directly activate this channel, triggering a Ca2+ influx and activating the microglia. Subsequently, the NF-κB signalling pathway is activated; NF-κB enters the cell nucleus and initiates the transcription of certain pro-inflammatory factors. This upregulates the expression of effector molecules such as IL-1β, IL-6, TNF-α, NO and ROS, thereby amplifying the inflammatory response (94). Concurrently, the toll-like receptor 4 signalling pathway independently participates in neuroinflammation through its adaptor protein (myeloid differentiation primary response 88), which similarly activates NF-κB (95,96). On the other hand, upon TRPV1 activation, neurons release signalling molecules including SP and CGRP. These molecules bind to corresponding receptors on the surface of microglia through paracrine mechanisms, indirectly promoting microglial activation (97,98). Furthermore, TRPV1 antagonism effectively inhibits microglial activation and reduces the release of inflammatory cytokines (99).

Abnormal activation of astrocytes primarily contributes to the maintenance of central sensitisation. Astrocytes express small amounts of TRPV1 on their surface. Upon activation of this channel, Ca2+ influx triggers signalling pathways such as NF-κB and MAPK, leading to the release of inflammatory factors (IL-6 and complement C3) and neuroactive substances (ATP, glutamate and GABA). Notably, activated astrocytes exhibit downregulation of glutamate-aspartate transporter and glutamate transporter-1. This leads to a reduced capacity to clear glutamate from the synaptic cleft, resulting in glutamate accumulation. Accumulated glutamate continuously activates postsynaptic AMPA/NMDA receptors, thereby stabilizing and prolonging the hyper-excitable state of neurons (100,101). Interventions targeting TRPV1 can inhibit astrocyte activation, restore glutamate clearance capacity and reverse central sensitisation (101).

Thus, microglia serve a central role in initiating and acutely amplifying sensitisation, while astrocytes are responsible for maintaining sensitisation and facilitating its transition to a chronic state. TRPV1 further serves an important regulatory role in this continuous process (Fig. 1B).

Participation in the inflammatory response and promotion the initiation of central sensitization

TRPV1 participates in the initiation and amplification of central inflammatory responses by regulating the release of inflammatory mediators and the activation of inflammatory signalling pathways.

During a migraine attack, TRPV1 activation promotes the release of prostaglandin E2 (PGE2) from neurons and glial cells. Upon binding to its receptors (EP1-EP4), PGE2 produces two effects. First, it phosphorylates TRPV1, thereby enhancing its sensitivity. Second, it promotes the release of glutamate and CGRP. These effects collectively form a positive feedback loop that drives central sensitisation (102). TRPV1 antagonists can inhibit PGE2 release and thus block this loop (103).

Furthermore, TRPV1 activation triggers a Ca2+ influx. This further activates two signalling pathways. The first is the CaMKII/NF-κB pathway, which promotes the transcription and release of inflammatory cytokines such as IL-1β, IL-6 and TNF-α (104). The second involves signalling cascades such as ERK1/2 and p38 MAPK, which promotes the release of inflammatory cytokines (including TNF-α, IL-1β and IL-6) and excitatory neurotransmitters (including glutamate, substance P and CGRP), thereby increasing neuronal excitability. Collectively, these two pathways drive central sensitisation (105,106). TRPV1 antagonists can thus inhibit the activation of the NF-κB pathway and reduce the expression of inflammatory factors. Combining them with MAPK pathway inhibitors can synergistically enhance the reversal of central sensitisation (107) (Fig. 1C).

Regulating synaptic plasticity to reshape pain transmission pathways

Changes in synaptic plasticity (particularly the formation of LTP) constitute the structural basis of central sensitisation. TRPV1 regulates synaptic plasticity through both presynaptic and postsynaptic mechanisms. Specifically, TRPV1 activation first drives the release of glutamate from presynaptic terminals. This process subsequently triggers the phosphorylation of postsynaptic NMDA/AMPA receptors and the maintenance of LTP. This sequence constitutes a temporal causal chain initiating central sensitisation (108-110).

At the presynaptic level, TRPV1 drives LTP establishment by regulating neurotransmitter release. As aforementioned, TRPV1 activation promotes the release of excitatory neurotransmitters such as CGRP, SP and glutamate. These neurotransmitters act upon corresponding receptors on the postsynaptic membrane, inducing Ca2+ influx and downstream signalling activation, thereby enhancing postsynaptic neuron excitability. Simultaneously, retrograde messengers released from the postsynaptic site provide feedback to the presynaptic site, further promoting neurotransmitter release. This positive feedback loop provides the necessary depolarization intensity and calcium signal accumulation for LTP formation.

At the postsynaptic level, TRPV1 contributes to LTP maintenance by regulating receptor function. The Ca2+ influx triggered by TRPV1 activation activates the ERK1/2 pathway, promoting phosphorylation of NMDA receptor NR1/NR2B subunits and enhancing receptor channel activity (111). Second, through a CaMKII-dependent pathway, it induces phosphorylation of the glutamate receptor 1 subunit at Ser831, thereby upregulating receptor single-channel conductance and membrane surface expression (112-114). Enhanced NMDA receptor function provides a sustained calcium signal source for synaptic plasticity, while upregulated AMPA receptor function directly increases synaptic transmission efficiency. Collectively, these mechanisms maintain the long-lasting stability of LTP. Therefore, TRPV1 antagonists can inhibit ERK1/2 activation, reduce the phosphorylation levels of NMDA/AMPA receptors, prevent LTP maintenance and reverse central sensitisation (115-117).

In summary, TRPV1 drives the establishment of LTP by regulating neurotransmitter release presynaptically; simultaneously, it maintains LTP by regulating receptor function postsynaptically. These two processes are temporally sequential and spatially coordinated, together constituting the complete mechanism by which TRPV1 regulates synaptic plasticity (Fig. 1D).

Recent advances in TRPV1-targeted migraine treatments

Given the role of TRPV1 in central sensitisation, interventions targeting this channel have become a new focus in migraine treatment research. The present section will go on to summarize clinical and animal studies regarding TRPV1 antagonists, TRPV1 agonists and gene regulation strategies for migraine treatment. Both PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Web of Science (https://www.webofscience.com/) data-bases were searched for literature published up to December 2025. Studies were included if they met the following criteria: i) Mechanistic and preclinical studies investigating the involvement of TRPV1 in pain through central sensitisation; ii) studies involving the trigeminal nerve or central pain pathways in migraine models or other chronic pain models; and iii) studies that included measures of TRPV1 regulation and central sensitisation. Studies focusing solely on peripheral non-neural tissues or lacking any indicators of central sensitisation were excluded.

TRPV1 antagonists

TRPV1 antagonists alleviate migraine by blocking channel activity and inhibiting central sensitisation. Research regarding this strategy has spanned natural products, synthetic small molecules and peptide derivatives.

In reference to natural sources and dual-target mechanisms, petasin and isopetasin from Tussilago farfara root extract may simultaneously inhibit TRPV1 and transient receptor potential anchor ankyrin 1. These compounds reduce neuropeptide release from trigeminal nerve terminals, thereby blocking the transmission of peripheral signals to the CNS (118). Similarly, the natural compound PINO reverses sensory neuron sensitisation by inhibiting the NF-κB/MAPK signalling pathway. This provides a promising direction for the application of novel TRPV1 antagonists (83).

Studies on specific antagonists have provided evidence for the inhibitory effects of capsazepine. Rosta et al (73) and Citak et al (77) separately determined that capsazepine may block TRPV1 activation induced by insulin or agonists. Its effects include inhibiting neurogenic inflammation and disrupting sensitized transmission in the trigeminal pathway. Studies on Johnson & Johnson series compounds found that JNJ-38893777 and JNJ-17203212 suppress excessive sensory neuron excitation and downstream neurovascular responses (119). At the molecular level, Fan et al (120) showed that SAF312, through synergistic action with cholesterol, stabilizes the closed conformation of the TRPV1 channel, thereby inhibiting its activation. Furthermore, peptide-based strategies have progressed; for example, the glucagon-like peptide-1 derivative exendin 20-29 selectively blocks capsaicin-induced TRPV1 activation without causing fever-associated side effects (121). In synthetic chemistry, 2-halophenylacetamide derivatives have exhibited notable TRPV1 antagonistic activity (122).

However, clinical translation faces challenges. Despite the aforementioned studies having demonstrated the marked potential of TRPV1 antagonists in terms of source diversity and molecular mechanisms, and some compounds, such as the novel TRPV1 modulator AMG8562, have been shown to circumvent the traditional side effect of hyperthermia in preclinical studies (123), translating laboratory discoveries into clinical applications for migraines remains difficult. The analgesic effects observed in preclinical animal models are difficult to replicate in migraine patients and the risk of target-associated increases in core body temperature persists (124,125). Despite basic research have demonstrating that TRPV1 inhibition reduces trigeminal pathway sensitisation, bridging the translational gap to develop safe and migraine-specific drugs remains a persistent challenge.

TRPV1 agonists

Unlike antagonists, agonists induce receptor desensitisation by continuously activating channels, keeping them in a prolonged inactivated state and thereby inhibiting central sensitisation. This strategy avoids side effects associated with long-term antagonist use, such as hyperthermia (126). Consequently, it offers unique advantages in the context of migraine prophylaxis.

As an established TRPV1 agonist, capsaicin has been extensively studied for its multi-target desensitisation mechanisms. A previous study demonstrated (127) that capsaicin induced degranulation of meningeal mast cells and a neuro-mediated inflammatory response by activating TRPV1. Topiramate, however, notably inhibited this process. Deng et al (128) further revealed that after capsaicin activated TRPV1 in DRG neurons, it upregulated sodium-potassium-chloride cotransporter 1 expression through the PKC and phosphorylated ERK pathway, leading to an increase in intracellular chloride concentration. This sensitizing effect can be reversed by subsequent channel desensitisation under sustained agonist stimulation. Furthermore, capsaicin can inhibit the voltage-gated calcium channel type 3 T-type calcium channel by almost two-fold, an effect independent of desensitisation mechanisms (129). In a comparative study, Krivoshein et al (130) used capsaicin as a positive control and demonstrated that the endocannabinoid arachidonoyl ethanolamine can potently inhibit TRPV1-mediated firing in the long term, although a transient excitatory effect was observed during the initial phase of administration.

Clinical translation of capsaicin remains unsatisfactory. First, the intense initial burning sensation associated with high-concentration topical capsaicin formulations is a reported adverse reaction (131). Second, even if patients tolerate treatment, continuous administration is required for numerous weeks; after discontinuation, nerve fibres regenerate, leading to pain recurrence (132), necessitating long-term or even life-long medication, making compliance the primary challenge.

Other agonists and desensitisation strategies continue to expand molecular diversity in this field. The potent agonist resiniferatoxin (RTX) upregulates expression of pain-sensitisation molecules such as TRPV1, brain-derived neurotrophic factor and voltage-gated sodium channel subtypes 1.3 and 1.7 by activating the p38 MAPK pathway in DRGs (133). However, initial RTX administration is associated with marked local irritation, manifested as acute burning pain and inflammatory reactions. This has somewhat impacted the early clinical experience. Despite this, owing to its unique targeted pharmacological advantages, RTX still holds value in clinical translation research (134,135). Alsalem et al (136) determined that the non-irritant agonists arvanil and olvanil induce TRPV1 desensitisation. Notably, arvanil-induced desensitisation can be reversed by bradykinin through the EP4 pathway, resulting in resensitisation. In addition, the dietary compound 8-gingerol induces TRPV1 internalization or degradation through a 'first activation, then desensitisation' mechanism. Its analgesic effect is entirely dependent on this channel (137). Furthermore, with regard to novel agonists, one research team developed a new partial agonist, namely 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl) piperazine-1-carboxamide (known as CPIPC). This compound targets the Arg557 residue and is capable of concentration-dependently activating the channel and inducing desensitisation. Oral administration of this agonist alleviates inflammatory pain and effectively blocks peripheral-to-central sensitisation transmission (138).

Other therapeutic strategies targeting TRPV1

Gene regulation strategies involve epigenetic interventions or modifications of cis-acting elements to modulate TRPV1 expression in the central and peripheral nervous systems at the transcriptional level. Ghosh et al (139) demonstrated that the histone methyltransferase G9a in DRGs bidirectionally regulates TRPV1 expression; inhibition of G9a reverses inflammation-driven TRPV1 upregulation and pain hypersensitivity. An additional study regarding orofacial inflammation found that this pathological state downregulates DNA methyltransferase 1/3a expression in the TG. This leads to hypomethylation of the TRPV1 promoter, thereby activating its expression and driving central sensitisation (140). Lai et al (141) demonstrated that following nerve injury, T-box transcription factor 5 (Tbx5) accumulates and recruits GATA-binding protein 4 and bromo domain protein 4 (Brd4). These factors bind to the TRPV1 promoter, enriching histone H3 lysine 9 acetylation, thereby activating TRPV1 expression. This Tbx5/Brd4 axis provides a key reference for the mechanism underlying TRPV1 upregulation in the TNC region of a migraine. Furthermore, Price et al (142) reported that the human SINE-VNTR-Alu retrotransposon serves as a functional cis-regulatory element for TRPV1. Knockout of this element markedly downregulated TRPV1 expression, providing a potential target for species-specific interventions based on gene editing.

RNA interference technology can further specifically inhibit TRPV1 mRNA expression through small interfering RNA or microRNA (miRNA). In a nitroglycerininduced chronic migraine model, researchers found that miR-155-5p expression was upregulated in the TNC region. This molecule triggered inflammatory responses and central sensitisation through targeted inhibition of silenced information regulator 1 (SIRT1). The use of miR-155-5p antagonists or SIRT1 activators can reverse this process (143). Furthermore, Li et al (144) demonstrated that miR-199 directly targeted TRPV1 and downregulated its expression. An additional study by Li et al (145) found that activation of NF-κB subunit 1 signalling pathway downregulated the expression of miR-375 and miR-455. This promoted an inhibitory effect on the 3′ untranslated region of TRPV1 mRNA, leading to TRPV1 upregulation.

In summary, TRPV1 antagonists can effectively block central sensitisation but have shown poor efficacy in clinical translation and may cause hyperthermia. Agonists achieve prophylactic treatment by inducing channel desensitisation, thereby avoiding the aforementioned issues associated with antagonists. However, agonists often cause severe burning pain and inflammatory reactions in the initial stages and symptoms are prone to recurrence after discontinuation. Gene regulation and RNA interference strategies can modulate TRPV1 expression at the transcriptional level and have shown promise in chronic migraine models. However, the majority are currently in the preclinical stage, with delivery efficiency, off-target risks and long-term safety remaining notable obstacles. Overall, each strategy exhibits both advantages and limitations. Future research should therefore seek to make breakthroughs in targeting precision, delivery methods and safety assessment (Table I).

Table I Summary of TRPV1-targeting migraine treatments and interventions.

Table I

Summary of TRPV1-targeting migraine treatments and interventions.

Name of drug/intervention		Type	Mechanism of action	(Refs.)
TRPV1 antagonist	Capsazepine	Synthetic small molecules	Blocks TRPV1 activation, inhibits CGRP release and suppresses neurogenic inflammation	(73,77)
	PINO	Natural compounds	Inhibits the NF-κB/MAPK pathway and reverses receptor sensitisation	(83)
	Petasin/isopetasin	Natural product (Tussilago farfara root extract)	Dually inhibits TRPV1/TRPA1, reducing CGRP release	(118)
	JNJ-38893777	Synthetic small molecules	Reduces c-Fos expression and CGRP release in the brainstem	(119)
	JNJ-17203212	Synthetic small molecules	Reduces c-Fos expression and CGRP release in the brainstem	(119)
	SAF312	Synthetic small molecules	Works collectively with cholesterol to stabilize the channel in its closed conformation	(120)
	Exendin 20-29	GLP-1 analogues	Selectively blocks capsaicin activation without causing side effects on body temperature	(121)
	2-Halophenylacetamide derivatives	Synthetic small molecules	Exhibits potent TRPV1 antagonistic activity	(122)
TRPV1 agonist	Capsaicin	Natural products	Induces desensitisation upon activation of TRPV1; dually inhibits Cav3 T-type calcium channels; upregulates NKCC1 through the PKC/p-ERK pathway	(127-130)
	RTX	Potent agonist	Activates the p38 MAPK pathway in DRGs and upregulates pain sensitisation molecules such as TRPV1, BDNF and Nav1.3/1.7	(133)
	Arvanil	Non-irritant agonists	Induces TRPV1 desensitisation, which can be reversed by bradykinin	(136)
	Olvanil	Non-irritant agonists	Induces TRPV1 desensitisation	(136)
	8-Gingerol	Dietary natural product	Activates first and then desensitises, inducing TRPV1 internalisation/degradation	(137)
	CPIPC	Novel partial agonist	Targets the Arg557 residue, concentration-dependently activates the receptor and induces desensitisation	(138)
Gene regulation	G9a inhibitor	Epigenetic Intervention	Inhibits the histone methyltransferase G9a, reversing inflammation-driven TRPV1 upregulation and pain hypersensitivity	(139)
	DNMT1/3a intervention	Epigenetic intervention	Restores methylation of the TRPV1 promoter, thereby suppressing its expression	(140)
	Interference with the Tbx5/Brd4 axis	Transcriptional regulation	Inhibits Tbx5 recruitment of GATA4 and Brd4, reducing H3K9Ac enrichment at the TRPV1 promoter	(141)
	SVA type D retrotransposon knockout	Gene Editing	Knocks out cis-regulatory elements to downregulate TRPV1 expression	(142)
RNA interference	miR-155-5p antagonist	miRNA intervention	Inhibits SIRT1, reversing inflammatory responses and central sensitisation	(143)
	miR-199	miRNA intervention	Directly targets TRPV1 mRNA and downregulates its expression	(144)
	miR-375/miR-455	miRNA intervention	Targets the 3′-UTR of TRPV1 mRNA and reverses NF-κB1-mediated de-repression	(145)

[i] TRPV1, transient receptor potential vanilloid 1; TRPA1, transient receptor potential ankyrin 1; CGRP, calcitonin gene-related peptide; c-Fos, cellular proto-oncogene Fos; GLP-1, glucagon-like peptide-1; Cav3, voltage-gated calcium channel 3; PKC, protein kinase C; p-ERK, phosphorylated ERK; NKCC1, sodium-potassium-chloride cotransporter 1; RTX, resiniferatoxin; DRG, dorsal root ganglion; BDNF, brain-derived neurotrophic factor; Nav, voltage-gated sodium channel; DNMT, DNA methyltransferase; Tbx5, T-box transcription factor 5; Brd4, bromodomain-containing protein 4; SVA, SINE-VNTR-Alu retrotransposon; miRNA/miR, micro RNA; mRNA, messenger RNA; SIRT1, silent information regulator 1; 3′-UTR, 3′ untranslated region; NF-κB1, NF-κ subunit 1; GATA4, GATA binding protein 4; PINO, pinocembrin-7-O-3-O-galloyl-4,6-hexahydroxydiphenoyl-β-D-glucoside; JNJ, Johnson & Johnson; CPIPC, 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl) piperazine-1-carboxamide.

Conclusions

Within the present review, the key mechanisms underlying the chronicisation of migraines were systematically elucidated. The present review focused on TRPV1-mediated central sensitisation thus provided a basis for clinically stratified interventions. By analysing the advantages and disadvantages of antagonists, agonists and gene regulation, the present identified translational bottlenecks (such as the side effect of hyperthermia) and strategies to circumvent them. This may therefore direct targeted drug development and harbour clear clinical value. Despite this, a number of key issues remain to be addressed in current research.

Limitations of existing research

Although current studies regarding the role of TRPV1-mediated central sensitisation in migraine pathogenesis have established its central regulatory function, numerous key questions remain. First, the precise regulatory mechanisms of TRPV1 have yet to be thoroughly elucidated at the molecular level, for example, the specific phosphorylation sites of TRPV1 by different kinases (PKC, PKA and CaMKII) and their functional differences remain incompletely understood (146,147). Furthermore, the activation patterns and downstream signalling differences of the channel across numerous cell types (including neurons, microglia and astrocytes) require further investigation (97,147). These gaps limit the ability to precisely intervene in TRPV1 function. Second, there is a marked translational gap between existing animal models and clinical migraines. The majority of studies utilize models of inflammatory pain or nerve injury and there is a lack of ideal models capable of simulating the spontaneous onset and chronic progression of migraines. Furthermore, the pathological characteristics of the widely used nitroglycerin-induced model have yet to be validated for their correspondence with clinical migraines (148-151).

Building upon this, the clinical translation of TRPV1-targeted drugs also faces unique challenges. TRPV1 antagonists exert their effects by blocking pain signal transmission, whereas agonists induce receptor desensitisation through excessive activation. The cellular basis for the latter lies in the fact that sustained activation triggers Ca2+ influx overload, altered phosphorylation and endocytosis-mediated degradation, ultimately leading to long-term functional inactivation of the receptor (152). Although their mechanisms are opposite, both can alleviate migraines, meaning there is no single primary mechanism (153).

To the best of our knowledge, no clinical trials have directly compared the relative efficacy of the two approaches. Existing evidence simply suggests that bidirectional modulation of the same target holds analgesic potential; however, neither approach has become an established therapy. Their clinical translation faces numerous challenges. Antagonist development is hampered by targeted side effects such as hyperthermia and impaired heat perception (154-156), while the desensitisation strategy of agonists, though capable of avoiding some side effects, notably increases the difficulty of clinical management due to the irritant response during the initial activation phase (73,157,158). Furthermore, the heterogeneity in TRPV1 expression and function across different disease courses, subtypes and comorbid conditions of migraine remains unclear, making it difficult to support the development of precision intervention strategies (159-161).

Future research directions

At a basic research level, in-depth analysis of the molecular mechanisms underlying TRPV1-mediated central sensitisation is necessary. The present review recommends use of single-cell sequencing technology to elucidate the subpopulation heterogeneity of TRPV1-positive neurons in the TNC region (162,163), generate cell-type-specific TRPV1 conditional knockout mice to clarify the role of TRPV1 in different cell types in migraine chronicity (164) and to investigate cross-regulatory networks between TRPV1, glial cell activation and neuroinflammation to identify novel molecular targets for clinical research (165).

At the clinical research level, the focus is on developing novel TRPV1-targeted drugs with high selectivity and minimal side effects. To address the translational challenges associated with TRPV1 antagonists, future efforts should focus on developing modally selective or preferential antagonists. By modulating the conformational dynamics of the channel protein, such drugs can specifically block pain signalling pathways without interfering with thermoregulatory functions (166,167). Concurrently, adverse reactions can be reduced through structural modifications and targeted delivery systems, and partial agonists or preferential modulators can be explored to precisely regulate receptor activity (168). TRPV1 PET tracers should be developed for the non-invasive assessment of central sensitisation in patients (169,170). Research into personalised migraine treatment based on TRPV1 genotype or expression levels should also be pursued (171). Concurrently, large-scale, multicentre clinical trials are needed to validate the efficacy and safety of targeted drugs and advance their clinical translation.

Availability of data and materials

Not applicable.

Authors' contributions

MZ was responsible for drafting the manuscript and creating the table and figure. YP and YZ provided key insights and contributed to the drafting of the manuscript. JH was responsible for literature searches, inclusion and exclusion criteria as well as literature organization and participated in the revision process. SL and HT refined the research concept and revised the final draft. BF and XB reviewed the manuscript and provided critical feedback. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

Funding

The present review was supported by the Sichuan Provincial Science and Technology Program (grant no. 2024YFFK0101), the Luzhou Municipal Science and Technology Program (grant no. 2023JYJ012) and the Innovation Team of the Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University (grant no. 2022-CXTD-05).

References