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Melatonin in Chronic Pain Syndromes

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Melatonin is a neurohormone synthesized in the pineal gland and extrapineal structures and has a number of functions, including chronobiotic, antioxidant, oncostatic, immunomodulatory, normothymic, and anxiolytic actions, the abilities to affect the cardiovascular system and the gastrointestinal tract and take part in reproductive functions, and a role in regulating substance metabolism and body weight. In addition, recent studies have demonstrated the efficacy of melatonin in relation to pain syndromes. We present here a review of studies of the use of melatonin in fibromyalgia, headaches, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis. The possible mechanisms mediating the analgesic properties of melatonin are discussed. On the one hand, normalization of circadian rhythms, which are inevitably deranged by chronic pain syndromes, improves sleep and activates the intrinsic adaptive potential of melatonin; on the other, data have been obtained showing that melatonin has independent analgesic influences mediated via melatonin receptors and various neurotransmitter systems.

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References

  1. R. J. Lucas, G. S. Lall, A. E. Allen, and T. M. Brown, “How rod, cone, and melanopsin photoreceptors come together to enlighten the mammalian circadian clock,” Prog. Brain Res., 199, 1–18 (2012), doi: https://doi.org/10.1016/b978-0-444-59427-3.00001-0.

    Article  CAS  PubMed  Google Scholar 

  2. V. Srinivasan, S. R. Pandi-Perumal, G. J. Maestroni, et al., “Role of melatonin in neurodegenerative diseases,” Neurotox Res. 7, 293–318 (2005), doi: https://doi.org/10.1007/bf03033887.

    Article  CAS  PubMed  Google Scholar 

  3. S. R. Pandi-Perumal, V. Srinivasan, G. J. M. Maestroni, et al., “Melatonin: Nature’s most versatile biological signal?” FEBS J., 273, 2813–2838 (2006), doi: https://doi.org/10.1111/j.1742-4658.2006.05322.x.

    Article  CAS  PubMed  Google Scholar 

  4. L. Yongliang, H. Hongwen, and H. Fang, “Melatonin in pain modulation: analgesic or proalgesic?” Pain Stud. Treat., 2, 50–55 (2014), doi: https://doi.org/10.4236/pst.2014.22009.

    Article  Google Scholar 

  5. D. A. Golombek, E. Escolar, L. J. Burin, et al., “Time dependent melatonin analgesia in mice: inhibition by opiate or benzodiazepine antagonism,” Eur. J. Pharmacol., 194, 25–30 (1991), doi: https://doi.org/10.1016/0014-2999(91)90119-b.

    Article  CAS  PubMed  Google Scholar 

  6. C. X. Yu, B. Zhu, S. F. Xu, et al., “The analgesic effects of peripheral and central administration of melatonin in rats,” Eur. J. Pharmacol., 403, 49–53 (2000), doi: https://doi.org/10.1016/s0014-2999(00)00421-0.

    Article  CAS  PubMed  Google Scholar 

  7. S. M. El-Shenawy, O. M. Abdel-Salam, A. R. Baiuomy, et al., “Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat,” Pharmacol. Res., 46, No. 3, 235–243 (2002), doi: https://doi.org/10.1016/s1043-6618(02)00094-4.

    Article  CAS  PubMed  Google Scholar 

  8. E. Esposito, I. Paterniti, E. Mazzon, et al., “Melatonin reduces hyperalgesia associated with inflammation,” J. Pineal Res., 49, No. 4, 321–331 (2010), doi: https://doi.org/10.1111/j.1600-079x.2010.00796.x.

    Article  CAS  PubMed  Google Scholar 

  9. M. Mantovani, R. Pértile, J. B. Calixto, et al., “Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-D-aspartate receptors and the L-arginine-nitric oxide pathway,” Neurosci Lett., 343, No. 1, 1–4 (2003), doi: https://doi.org/10.1016/s0304-3940(03)00306-9.

    Article  CAS  PubMed  Google Scholar 

  10. Y, Tu, R. Q. Sun, and W. D. Willis, “Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats,” Pain, 109, No. 3, 340–350 (2004), doi: https://doi.org/10.1016/j.pain.2004.01.027.

  11. A. Ulugol, D. Dokmeci, G. Guray, et al., “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, No. 14, 1592–1597 (2006), doi: https://doi.org/10.1016/j.lfs.2005.07.002.

    Article  CAS  PubMed  Google Scholar 

  12. M. R. Masruha, D. S. de Souza Viera, T. S. Minett, et al., “Low urinary 6-sulphatoxy-melatonin concentrations in acute migraine,” J. Headache Pain, 9, 221–234 (2008), doi: https://doi.org/10.1007/s10194-008-0047-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. M. F. Peres, E. Zukerman, F. da Cunha Tanuri, et al., “Melatonin, 3 mg, is effective for migraine prevention,” Neurology, 63, 757 (2004), doi: https://doi.org/10.1212/01.wnl.0000134653.35587.24.

    Article  CAS  PubMed  Google Scholar 

  14. G. R. Tabeeva, A. V. Sergeev, and S. A. Gromova, “The potential for the prophylactic treatment of migraine with the MT1 and MT2 receptor agonist/5-HT2C receptor antagonist agomelatin (Valdoxan),” Zh. Nevrol. Psikhiat., 111, No. 9, 32–36 (2011).

    CAS  Google Scholar 

  15. M. F. P. Peres, M. R. Masruha, E. Zukerman, et al., “Potential therapeutic use of melatonin in migraine and other headache disorders,” Expert Opin. Investig. Drugs, 15, No. 4, 367–375 (2006), doi: https://doi.org/10.1517/13543784.15.4.367.

    Article  CAS  PubMed  Google Scholar 

  16. M. Leone, D. D’Amico, F. Moschiano, et al., “Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups,” Cephalalgia, 16, 494–496 (1996), doi: https://doi.org/10.1046/j.1468-2982.1996.1607494.x.

    Article  CAS  PubMed  Google Scholar 

  17. T. Pringsheim, E. Magnoux, C. F. Dobson, et al., “Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study,” Headache. 42, 787–792 (2002), doi: https://doi.org/10.1046/j.1526-4610.2002.02181.x.

    Article  PubMed  Google Scholar 

  18. S. Miano, P. Parisi, A. Pellicci, et al., “Melatonin to prevent migraine or tension-type headache in children,” Neurol. Sciences, 29, No. 4, 285–287 (2008), doi: https://doi.org/10.1007/s10072-008-0983-5.

    Article  Google Scholar 

  19. Yu. M. Kurganova and A. B. Danilov, “The role of melatonin in the treatment of chronic spinal pain,” Zh. Nevrol. Psikhiat., 115, No. 4, 30–35 (2015).

    Article  Google Scholar 

  20. W. Z. Lu, K. A. Gwee, S. Moochhalla, and K. Y. Ho, “Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study,” Aliment. Pharmacol. Ther., 22, No. 10, 927–934 (2005), doi: https://doi.org/10.1111/j.1365-2036.2005.02673.x.

    Article  CAS  PubMed  Google Scholar 

  21. S. Mozaffari, R. Rahimi, and M. Abdollahi, “Implications of melatonin therapy in irritable bowel syndrome: a systematic review,” Curr. Pharm. Des., 16, No. 33, 3646–3655 (2010), doi: https://doi.org/10.2174/138161210794079254.

    Article  CAS  PubMed  Google Scholar 

  22. L. Saha, S. Malhotra, S. Rana, et al., “A preliminary study of melatonin in irritable bowel syndrome,” J. Clin. Gastroenterol., 41, No. 1, 29–32 (2007), doi: https://doi.org/10.1097/mcg.0b013e31802df84c.

    Article  CAS  PubMed  Google Scholar 

  23. G. H. Song, P. H. Leng, K. A. Gwee, et al., “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), doi: https://doi.org/10.1136/gut.2004.062034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. W. Z. Lu, K. A. Gwee, S. Moochhalla, and K. Y. Ho, “Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study,” Alim. Pharmacol. Ther., 22, No. 10, 927–934 (2005), doi: https://doi.org/10.1111/j.1365-2036.2005.02673.x.

    Article  CAS  Google Scholar 

  25. C. Chojnacki, E. Walecka-Kapica, K. Lokieć, et al., “Influence of melatonin on symptoms of irritable bowel syndrome in postmenopausal women,” Endokrynol. Pol., 64, 114–120 (2013).

    CAS  PubMed  Google Scholar 

  26. E. B. Klerman, D. L. Goldenberg, E. N. Brown, et al., “Circadian rhythms of women with fibromyalgia,” J. Clin. Endocrinol. Metab., 86, 1034–1039 (2001), doi: https://doi.org/10.1210/jc.86.3.1034.

    CAS  PubMed  Google Scholar 

  27. J. Wikner, U. Hirsch, L. Wetterberg, and S. Rojdmark, “Fibromyalgia – a syndrome associated with decreased nocturnal melatonin secretion,” Clin. Endocrinol. (Oxf.), 49, 179–183 (1998), doi: https://doi.org/10.1046/j.1365-2265.1998.00503.x.

    Article  CAS  Google Scholar 

  28. Ya. I. Levin, “Melatonin (Melaxen) in neurological practice,” Consilium Medicum, 2, 111–115 (2012).

    Google Scholar 

  29. G. Citera, M. A. Arias, J. A. Maldonado-Cocco, et al., “The effect of melatonin in patients with fibromyalgia: a pilot study,” Clin. Rheumatol., 19, 9–13 (2000), doi: https://doi.org/10.1007/s100670050003.

    Article  CAS  PubMed  Google Scholar 

  30. S. A. Hussain, I. I. Al-Khalifa, N. A. Jasim, and F. I. Gorial, “Adjuvant use of melatonin for treatment of fibromyalgia,” J. Pineal Res., 50, 267–271 (2011), doi: https://doi.org/10.1111/j.1600-079x.2010.00836.x.

    Article  PubMed  Google Scholar 

  31. S. A. de Zanette, R. Vercelino, G. Laste, 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., (2014), doi: https://doi.org/10.1186/2050-6511-15-40.

  32. M. Cutolo, G. J. M. Maestroni, K. Otsa, et al., “Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison,” Ann. Rheum. Dis., 64, 2:212-216 (2005), doi: https://doi.org/10.1136/ard.2004.023416.

  33. M. Afkhamizadeh, M. Sahebari, and S. R. Seyyed-Hoseini, “Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: a cross-sectional study,” Rheumatol. Internat. (2014), doi: https://doi.org/10.1007/s00296-013-2930-x.

  34. M. Cutolo and G. J. M. Maestroni, “The melatonin-cytokine connection in rheumatoid arthritis,” Ann. Rheum. Dis., 64, 8:1109–1111 (2005), doi: https://doi.org/10.1136/ard.2005.038588 (2005).

  35. D. S. Rudra, U. Pal, N. C. Maiti, et al., “Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site,” J. Pineal Res., 54, 4:398–405 (2013), doi: https://doi.org/10.1111/jpi.12034.

  36. V. Srinivasan, E. C. Lauterbach, K. Y. Ho, et al., “Melatonin in antinociception: its therapeutic applications,” Curr. Neuropharmacol., 112, No. 10, No. 2, 167–178 (2012), doi: 10.2174|157015912800604489/

  37. J. Vanecek, “Cellular mechanisms of melatonin action,” Physiol. Rev., 78, No. 3, 687–721 (1998).

    CAS  PubMed  Google Scholar 

  38. P. K. Zahn, T. Lansmann, E. Berger, et al., “Gene expression and functional characterization of melatonin receptors in the spinal cord of the rat: implications for pain modulation,” J. Pineal Res., 35, No. 1, 24–31 (2003), doi: https://doi.org/10.1034/j.1600-079x.2003.00047.x.

    Article  CAS  PubMed  Google Scholar 

  39. M. Wilhelmsen, I. Amirian, R. J. Reiter, et al., “Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies,” J. Pineal Res., 51, 3:270–277 (2011), doi: https://doi.org/10.1111/j.1600-079x.2011.00895.x.

  40. M. Lopez-Canul, E. Palazzo, S. Dominguez-Lopez, et al., “Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways,” Pain, 156, No. 2, 305–317 (2015), doi: https://doi.org/10.1097/01.j.pain.0000460311.71572.5f.

    Article  CAS  PubMed  Google Scholar 

  41. D. Steinhilber, M. Brungs, O. Werz, et al., “The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes,” J. Biol. Chem., 270, No. 13, 7037–7040 (1995), doi: https://doi.org/10.1074/jbc.270.13.7037

    Article  CAS  PubMed  Google Scholar 

  42. L. M. Wang, N. A. Suthana, D. Chaudhury, et al., “Melatonin inhibits hippocampal long-term potentiation,” Eur. J. Neurosci., 22, No. 9, 2231–2237 (2005), doi: https://doi.org/10.1111/j.1460-9568.2005.04408.x.

    Article  PubMed  PubMed Central  Google Scholar 

  43. A. Ayar, J. M. Duncan, M. Ozcan, and H. Kelestimur, “Melatonin inhibits high voltage activated calcium currents in cultured rat dorsal root ganglion neurons,” Neurosci. Lett., 313, No. 1–2, 73–77 (2001), doi: https://doi.org/10.1016/s0304-3940(01)02188-7.

    Article  CAS  PubMed  Google Scholar 

  44. M. Wilhelmsen, I. Amirian, R. J. Reiter, et al., “Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies,” J. Pineal Res., 51, 3:270–277 (2011), doi: https://doi.org/10.1111/j.1600-079x.2011.00895.x.

  45. F. Xu, J. C. Li, K. C. Ma, et al., “Effects of melatonin on hypothalamic gamma-aminobutyric acid, aspartic acid, glutamic acid, beta-endorphin and serotonin levels in male mice,” Biol Signals, 4, 225–231 (1995).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Yu. M. Kurganova.

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Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 115, No. 10, Iss. II, For the Practicing Doctor, pp. 47–54, October, 2015.

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Kurganova, Y.M., Danilov, A.B. Melatonin in Chronic Pain Syndromes. Neurosci Behav Physi 47, 806–812 (2017). https://doi.org/10.1007/s11055-017-0472-5

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