Pain control by melatonin: Physiological and pharmacological effects (Review)

Chen,Wei‑Wei; Zhang,Xia; Huang,Wen‑Juan

doi:10.3892/etm.2016.3565

Pain control by melatonin: Physiological and pharmacological effects (Review)

Authors:
- Wei‑Wei Chen
- Xia Zhang
- Wen‑Juan Huang
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Affiliations: Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China
Published online on: August 3, 2016 https://doi.org/10.3892/etm.2016.3565
Pages: 1963-1968
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pain and anxiety are the most common neurological responses to many harmful or noxious stimuli and their management clinically is often challenging. Many of the frequently used morphine‑based drugs, non‑steroid anti‑inflammatory drugs and acetaminophen, while efficient for treating pain, lead to patients suffering from several unwanted side effects. Melatonin, produced from the pineal body is a hormone of darkness, is involved in the control of circadian rhythms, and exerts a number of pharmacological effects. Melatonin mediates its actions through MT1/MT2 melatonin receptors on the cell membrane and also through RZR/ROR nuclear orphan receptors. Chronic pain syndromes are often associated with the desynchronization of circadian and biological rhythms, which also cause disturbances in the sleep‑wake cycle. Melatonin‑mediated analgesic effects seem to involve β‑endorphins, GABA receptor, opioid receptors and the nitric oxide‑arginine pathway. The effectiveness of melatonin as an analgesic and anxiolytic agent has been demonstrated in various animal models of pain and this led to the use of melatonin clinically in different pathological conditions and also in patients undergoing surgery. Melatonin was found to be effective in many of these cases as an anxiolytic and analgesic agent, indicating its clinical application.

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1	Bolten WW, Gross M, Brabant T, Weck V and Labenz J: Individual pain treatment with NSAIDs. MMW Fortschr Med. 15559–60. (62)2013. View Article : Google Scholar : PubMed/NCBI
2	Ennis ZN, Dideriksen D, Vaegter HB, Handberg G and Pottegard A: Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. Basic Clin Pharmacol Toxicol. 118:184–189. 2016. View Article : Google Scholar : PubMed/NCBI
3	Pasternak GW: When it comes to opiates, just say NO. J Clin Invest. 117:3185–3187. 2007. View Article : Google Scholar : PubMed/NCBI
4	García Rodríguez LA and Jick H: Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 343:769–772. 1994. View Article : Google Scholar : PubMed/NCBI
5	Wiech K and Tracey I: The influence of negative emotions on pain: Behavioral effects and neural mechanisms. Neuroimage. 47:987–994. 2009. View Article : Google Scholar : PubMed/NCBI
6	Basbaum AI, Bautista DM, Scherrer G and Julius D: Cellular and molecular mechanisms of pain. Cell. 139:267–284. 2009. View Article : Google Scholar : PubMed/NCBI
7	Tovote P, Fadok JP and Lüthi A: Neuronal circuits for fear and anxiety. Nat Rev Neurosci. 16:317–331. 2015. View Article : Google Scholar : PubMed/NCBI
8	Wilhelmsen M, Amirian I, Reiter RJ, Rosenberg J and Gögenur I: Analgesic effects of melatonin: A review of current evidence from experimental and clinical studies. J Pineal Res. 51:270–277. 2011. View Article : Google Scholar : PubMed/NCBI
9	Frange C, Hachul H, Tufik S and Andersen ML: Circadian rhythms, insomnia and osteoarthritis pain. Chronobiol Int. 32:1323–1324. 2015. View Article : Google Scholar : PubMed/NCBI
10	Junker U and Wirz S: Review article: Chronobiology: Influence of circadian rhythms on the therapy of severe pain. J Oncol Pharm Pract. 16:81–87. 2010. View Article : Google Scholar : PubMed/NCBI
11	Lucas RJ, Lall GS, Allen AE and Brown TM: How rod, cone, and melanopsin photoreceptors come together to enlighten the mammalian circadian clock. Prog Brain Res. 199:1–18. 2012. View Article : Google Scholar : PubMed/NCBI
12	Srinivasan V, Lauterbach EC, Ho KY, Acuña-Castroviejo D, Zakaria R and Brzezinski A: Melatonin in antinociception: Its therapeutic applications. Curr Neuropharmacol. 10:167–178. 2012. View Article : Google Scholar : PubMed/NCBI
13	Danilov A and Kurganova J: Melatonin in chronic pain syndromes. Pain Ther. 5:1–17. 2016. View Article : Google Scholar : PubMed/NCBI
14	Reiter RJ: Melatonin: The chemical expression of darkness. Mol Cell Endocrinol. 79:C153–C158. 1991. View Article : Google Scholar : PubMed/NCBI
15	Pickard GE: Circadian rhythm of nociception in the golden hamster. Brain Res. 425:395–400. 1987. View Article : Google Scholar : PubMed/NCBI
16	Srinivasan V, PandiPerumal SR, Spence DW, Moscovitch A, Trakht I, Brown GM and Cardinali DP: Potential use of melatonergic drugs in analgesia: Mechanisms of action. Brain Res Bull. 81:362–371. 2010. View Article : Google Scholar : PubMed/NCBI
17	Axelrod J and Wurtman RJ: Photic and neural control of indoleamine metabolism in the rat pineal gland. Adv Pharmacol 6 (Pt A). 157–166. 1968. View Article : Google Scholar
18	Moore RY: Neural control of the pineal gland. Behav Brain Res. 73:125–130. 1996. View Article : Google Scholar : PubMed/NCBI
19	Berson DM, Dunn FA and Takao M: Phototransduction by retinal ganglion cells that set the circadian clock. Science. 295:1070–1073. 2002. View Article : Google Scholar : PubMed/NCBI
20	Klein DC, Schaad NL, Namboordiri MA, Yu L and Weller JL: Regulation of pineal serotonin N-acetyltransferase activity. Biochem Soc Trans. 20:299–304. 1992. View Article : Google Scholar : PubMed/NCBI
21	Becker-André M, Wiesenberg I, Schaeren-Wiemers N, André E, Missbach M, Saurat JH and Carlberg C: Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 269:28531–28534. 1994.PubMed/NCBI
22	Mukherjee D, Roy SG, Bandyopadhyay A, Chattopadhyay A, Basu A, Mitra E, Ghosh AK, Reiter RJ and Bandyopadhyay D: Melatonin protects against isoproterenol-induced myocardial injury in the rat: Antioxidative mechanisms. J Pineal Res. 48:251–262. 2010. View Article : Google Scholar : PubMed/NCBI
23	Brydon L, Roka F, Petit L, de Coppet P, Tissot M, Barrett P, Morgan PJ, Nanoff C, Strosberg AD and Jockers R: Dual signaling of human Mella melatonin receptors via G(i2), G(i3), and G(q/11) proteins. Mol Endocrinol. 13:2025–2038. 1999. View Article : Google Scholar : PubMed/NCBI
24	Boutin JA, Audinot V, Ferry G and Delagrange P: Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci. 26:412–419. 2005. View Article : Google Scholar : PubMed/NCBI
25	Marseglia L, D'Angelo G, Manti S, Aversa S, Arrigo T, Reiter RJ and Gitto E: Analgesic, anxiolytic and anaesthetic effects of melatonin: New potential uses in pediatrics. Int J Mol Sci. 16:1209–1220. 2015. View Article : Google Scholar : PubMed/NCBI
26	Yu CX, Zhu B, Xu SF, Cao XD and Wu GC: The analgesic effects of peripheral and central administration of melatonin in rats. Eur J Pharmacol. 403:49–53. 2000. View Article : Google Scholar : PubMed/NCBI
27	Shavali S, Ho B, Govitrapong P, Sawlom S, Ajjimaporn A, Klongpanichapak S and Ebadi M: Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull. 64:471–479. 2005. View Article : Google Scholar : PubMed/NCBI
28	Lakin ML, Miller CH, Stott ML and Winters WD: Involvement of the pineal gland and melatonin in murine analgesia. Life Sci. 29:2543–2551. 1981. View Article : Google Scholar : PubMed/NCBI
29	Mease P: Fibromyalgia syndrome: Review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol Suppl. 75:6–21. 2005.PubMed/NCBI
30	Reiter RJ, AcunaCastroviejo D and Tan DX: Melatonin therapy in fibromyalgia. Curr Pain Headache Rep. 11:339–342. 2007. View Article : Google Scholar : PubMed/NCBI
31	Song GH, Leng PH, Gwee KA, Moochhala SM and Ho KY: Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: A randomised, double blind, placebo controlled study. Gut. 54:1402–1407. 2005. View Article : Google Scholar : PubMed/NCBI
32	Yousaf F, Seet E, Venkatraghavan L, Abrishami A and Chung F: Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: A qualitative systematic review of randomized trials. Anesthesiology. 113:968–976. 2010. View Article : Google Scholar : PubMed/NCBI
33	ElShenawy SM, AbdelSalam OM, Baiuomy AR, ElBatran S and Arbid MS: Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Pharmacol Res. 46:235–243. 2002. View Article : Google Scholar : PubMed/NCBI
34	Wang T, Li SR, Dai X, Peng YL, Chen Q and Wang R: Effects of melatonin on orphanin FQ/nociceptin-induced hyperalgesia in mice. Brain Res. 1085:43–48. 2006. View Article : Google Scholar : PubMed/NCBI
35	Golombek DA, Escolar E, Burin LJ, De Brito Sánchez MG and Cardinali DP: Time-dependent melatonin analgesia in mice: Inhibition by opiate or benzodiazepine antagonism. Eur J Pharmacol. 194:25–30. 1991. View Article : Google Scholar : PubMed/NCBI
36	Ulugol A, Dokmeci D, Guray G, Sapolyo N, Ozyigit F and Tamer M: Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: Possible involvements of the L-arginine-NO pathway and opioid system. Life Sci. 78:1592–1597. 2006. View Article : Google Scholar : PubMed/NCBI
37	Naguib M, Baker MT, Spadoni G and Gregerson M: The hypnotic and analgesic effects of 2-bromomelatonin. Anesth Analg. 97:763–768. 2003. View Article : Google Scholar : PubMed/NCBI
38	Mantovani M, Kaster MP, Pertile R, Calixto JB, Rodrigues AL and Santos AR: Mechanisms involved in the antinociception caused by melatonin in mice. J Pineal Res. 41:382–389. 2006. View Article : Google Scholar : PubMed/NCBI
39	Hernández-Pacheco A, Araiza-Saldaña CI, Granados-Soto V and Mixcoatl-Zecuatl T: Possible participation of the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway in the peripheral antinociception of melatonin. Eur J Pharmacol. 596:70–76. 2008. View Article : Google Scholar : PubMed/NCBI
40	vanGeijlswijk IM, Korzilius HP and Smits MG: The use of exogenous melatonin in delayed sleep phase disorder: A meta-analysis. Sleep. 33:1605–1614. 2010.PubMed/NCBI
41	Braam W, van Geijlswijk I, Keijzer H, Smits MG, Didden R and Curfs LM: Loss of response to melatonin treatment is associated with slow melatonin metabolism. J Intellect Disabil Res. 54:547–555. 2010. View Article : Google Scholar : PubMed/NCBI
42	Appleton RE and Gringras P: Melatonin: Helping to MEND impaired sleep. Arch Dis Child. 98:216–217. 2013. View Article : Google Scholar : PubMed/NCBI
43	Hartz I, Furu K, Bratlid T, Handal M and Skurtveit S: Hypnotic drug use among 0-17 year olds during 2004-2011: A nationwide prescription database study. Scand J Public Health. 40:704–711. 2012. View Article : Google Scholar : PubMed/NCBI
44	Heussler H, Chan P, Price AM, Waters K, Davey MJ and Hiscock H: Pharmacological and non-pharmacological management of sleep disturbance in children: An Australian Paediatric Research Network survey. Sleep Med. 14:189–194. 2013. View Article : Google Scholar : PubMed/NCBI
45	Burgess HJ, Revell VL, Molina TA and Eastman CI: Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg. J Clin Endocrinol Metab. 95:3325–3331. 2010. View Article : Google Scholar : PubMed/NCBI
46	Reiter RJ, Tan DX and Galano A: Melatonin: Exceeding expectations. Physiology (Bethesda). 29:325–333. 2014.PubMed/NCBI
47	Rovers J, Smits M and Duffy JF: Headache and sleep: Also assess circadian rhythm sleep disorders. Headache. 54:175–177. 2014. View Article : Google Scholar : PubMed/NCBI
48	Miano S, Parisi P, Pelliccia A, Luchetti A, Paolino MC and Villa MP: Melatonin to prevent migraine or tension-type headache in children. Neurol Sci. 29:285–287. 2008. View Article : Google Scholar : PubMed/NCBI
49	Peres MF, Zukerman E, da Cunha Tanuri F, Moreira FR and Cipolla-Neto J: Melatonin, 3 mg, is effective for migraine prevention. Neurology. 63:7572004. View Article : Google Scholar : PubMed/NCBI
50	Klerman EB, Goldenberg DL, Brown EN, Maliszewski AM and Adler GK: Circadian rhythms of women with fibromyalgia. J Clin Endocrinol Metab. 86:1034–1039. 2001. View Article : Google Scholar : PubMed/NCBI
51	Wikner J, Hirsch U, Wetterberg L and Röjdmark S: Fibromyalgia - a syndrome associated with decreased nocturnal melatonin secretion. Clin Endocrinol (Oxf). 49:179–183. 1998. View Article : Google Scholar : PubMed/NCBI
52	Citera G, Arias MA, MaldonadoCocco JA, Lázaro MA, Rosemffet MG, Brusco LI, Scheines EJ and Cardinalli DP: The effect of melatonin in patients with fibromyalgia: A pilot study. Clin Rheumatol. 19:9–13. 2000. View Article : Google Scholar : PubMed/NCBI
53	Hussain SA, AlKhalifa II, Jasim NA and Gorial FI: Adjuvant use of melatonin for treatment of fibromyalgia. J Pineal Res. 50:267–271. 2011. View Article : Google Scholar : PubMed/NCBI
54	deZanette SA, Vercelino R, Laste G, Rozisky JR, Schwertner A, Machado CB, Xavier F, de Souza IC, Deitos A, Torres IL, et al: Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: A phase II, randomized, double-dummy, controlled trial. BMC Pharmacol Toxicol. 15:402014. View Article : Google Scholar : PubMed/NCBI
55	Konturek SJ, Konturek PC, Brzozowski T and Bubenik GA: Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 58(Suppl 6): 23–52. 2007.PubMed/NCBI
56	Lu WZ, Gwee KA, Moochhalla S and Ho KY: Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: A double-blind placebo-controlled study. Aliment Pharmacol Ther. 22:927–934. 2005. View Article : Google Scholar : PubMed/NCBI
57	Mozaffari S, Rahimi R and Abdollahi M: Implications of melatonin therapy in irritable bowel syndrome: A systematic review. Curr Pharm Des. 16:3646–3655. 2010. View Article : Google Scholar : PubMed/NCBI
58	Saha L, Malhotra S, Rana S, Bhasin D and Pandhi P: A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol. 41:29–32. 2007. View Article : Google Scholar : PubMed/NCBI
59	Andersen LP, Werner MU, Rosenberg J and Gögenur I: A systematic review of peri-operative melatonin. Anaesthesia. 69:1163–1171. 2014. View Article : Google Scholar : PubMed/NCBI
60	Caumo W, Torres F, Moreira NL Jr, Auzani JA, Monteiro CA, Londero G, Ribeiro DF and Hidalgo MP: The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg. 105:1263–1271. 2007. View Article : Google Scholar : PubMed/NCBI
61	Mowafi HA and Ismail SA: Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia. Anesth Analg. 107:1422–1426. 2008. View Article : Google Scholar : PubMed/NCBI
62	Ismail SA and Mowafi HA: Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg. 108:1146–1151. 2009. View Article : Google Scholar : PubMed/NCBI