Role of Melatonin in the Regulation of Pain

Figures & data

Figure 1 The main synthesis and catabolic route of melatonin in vertebrates.

Note: The blue arrows represent the anabolic pathway of melatonin and the green arrows represent the catabolic pathway of melatonin.

Abbreviations: 5-HT, 5-hydroxytryptophan; TPH, tryptophan hydroxylase; AAAD, aromatic amino acid decarboxylase; SNAT, serotonin N-acetyltransferase; ASMT, acetylserotonin O-methyltransferase; NAS, N-acetylserotonin; 5-MT, 5-methoxytryptamine; AAAs, aryl acylamidases; CYPs, hepatic cytochromes; 6-HMT, 6-hydroxymelatonin; MAO-A, monoamine oxidase A; AFMK, N1-acetyl-N2-formyl-5-methoxykynurenamine; AMK, N1-acetyl-5-methoxykynuramine; 5-ML, 5-methoxychromitol.

Table 1 Antinociceptive Activity of Melatonin and Its Analogs

Pain Model	Species	Dose & Administration	Effect	References
O2^−evoked hyperalgesia	Rat	Melatonin,25–100mg/kg, i.p.	Antinociceptive activity	^Citation11
Formalin test	Rat	Melatonin, 30μg/10μL, intrathecally	Reduce flinching response	^Citation60
CFA	Rat	Melatonin, 50,60mg/kg, i.p.	Neuroprotective effects	^Citation61
		Melatonin, 50mg/kg, i.p.	Alters mechanical and thermal hyperalgesia	^Citation76
Morphine exposure	Rat	Melatonin, 10mg/kg, i.p.	Counter mechanical and thermal hyperalgesia	^Citation63
		Melatonin, 50mg/kg, i.p.	Reverse hyperalgesia	^Citation64
RIM	Rat	Melatonin, 2.5,5mg/kg, p.o.	Dose and/or time dependently analgesic effects	^Citation72
		Melatonin, 5mg/kg, p.o.	Improve motor activity	^Citation73
Arsenic	Rat	Melatonin, 10mg/kg, p.o.	Neuroprotective effects	^Citation83
Oxaliplatin	Rat	Melatonin, 20mg/kg, i.p.	Alleviate mechanical and thermal hyperalgesia	^Citation85
		Melatonin, 10mg/kg, i.p.	Alleviate pain behavior	^Citation86
Tail Flick Test Writhing Test Formalin Test	Mouse	Melatonin, 10mg/kg, s.c. Benzoyl-melatonin (BMT), 25mg/kg, s.c. Acetyl-melatonin, 50mg/kg, s.c.	BMT increases tail flick latency time, decreases number of writhes and reduces nociceptive response	^Citation87
CCI of sciatic nerve	Rat	Melatonin, 2.5, 5mg/kg, i.p.	Attenuate thermal hyperalgesia, cold allodynia	^Citation88
		Melatonin, 100mg/kg, i.p.	Increase pain threshold of mechanical allodynia and slightly increase threshold of thermal hyperalgesia.	^Citation89
		Melatonin, 5–10mg/kg, i.p.	Reduce thermal hyperalgesia	^Citation90
Oxaliplatin Streptozocin CCI of sciatic nerve	Rat	Agomelatine, 45 mg/kg, i.p.	Dose dependently reduce mechanical hypersensitivity	^Citation92
CCI of median nerve	Rat	Melatonin, 37.5, 75, 150, 300 mg/kg, p.o.	Dose dependently reduce mechanical hypersensitivity	^Citation95
CCI of sciatic nerve	Rat	Extracorporeal shock wave-assisted melatonin, 50,20mg/kg, i.p.	Superior to either one alone to improve pain	^Citation96,Citation97
Sciatic nerve cuff-implanted	Mouse	Melatonin, 100mg/kg, i.p.	Suppress mechanical allodynia and thermal hyperalgesia	^Citation17
PSL	Mouse	Piromelatine, 25, 50, or 100 mg/kg, i.p.	Antinociceptive	^Citation93

Figure 2 Schematic diagram of the primary mechanisms of melatonin and its analogs on neuropathic pain management.

Abbreviations: PGE2, prostaglandin E2; iNOS, inducible nitric oxide synthase; TNF, tumor necrosis factor; IL, interleukin; NE, norepinephrine.

Figure 3 Schematic diagram of the primary mechanisms for regulatory effects of melatonin and its analogs on neurons in pain.

Abbreviations: MT2, melatonin membrane receptor 2; TRPM2, transient receptor potential melastatin type 2; TRPV1, transient receptor potential vanilloid type 1; PLC, phospholipase C; PKC, protein kinase C; Ca²⁺_i, intracellular calcium; AchE, acetylcholinesterase; MAPK, mitogen-activated protein kinase; NOS, nitric oxide synthase; NO, nitric oxide; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; mGluRs, group II metabotropic glutamate receptors; NR, N-Methyl-D-aspartate receptor; JNK, c-Jun N-terminal kinase; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; CREB, cyclic adenosine monophosphate-response element binding protein; Tet1, spinal ten-eleven translocation methyl-cytosine dioxygenase 1; HMGB1, high-mobility group protein B1; PP2A, spinal serine-/threonine-specific phosphatase 2A; HDAC4, histone deacetylase 4; Ac, acetyl groups.

Esposito E, Paterniti I, Mazzon E, Bramanti P, Cuzzocrea S. Melatonin reduces hyperalgesia associated with inflammation. J Pineal Res. 2010;49(4):321–331. doi:10.1111/jpi.2010.49.issue-4

 Web of Science ®Google Scholar

Shin DJ, Jeong CW, Lee SH, Yoon MH. Receptors involved in the antinociception of intrathecal melatonin in formalin test of rats. Neurosci Lett. 2011;494(3):207–210. doi:10.1016/j.neulet.2011.03.014

 Web of Science ®Google Scholar

Laste G, Ripoll Rozisky J, Caumo W, Lucena da Silva Torres I. Short- but not long-term melatonin administration reduces central levels of brain-derived neurotrophic factor in rats with inflammatory pain. Neuroimmunomodulation. 2015;22(6):358–364. doi:10.1159/000380912

 PubMed Web of Science ®Google Scholar

Scarabelot VL, Medeiros LF, de Oliveira C, et al. Melatonin alters the mechanical and thermal hyperalgesia induced by orofacial pain model in rats. Inflammation. 2016;39(5):1649–1659. doi:10.1007/s10753-016-0399-y

 Web of Science ®Google Scholar

Song L, Wu C, Zuo Y. Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-D-aspartate receptors. BMC Anesthesiol. 2015;15:(12. doi:10.1186/1471-2253-15-12

 Web of Science ®Google Scholar

Rozisky JR, Scarabelot VL, Oliveira C, et al. Melatonin as a potential counter-effect of hyperalgesia induced by neonatal morphine exposure. Neurosci Lett. 2016;633:(77–81. doi:10.1016/j.neulet.2016.08.027

 Web of Science ®Google Scholar

Favero G, Trapletti V, Bonomini F, et al. Oral supplementation of melatonin protects against fibromyalgia-related skeletal muscle alterations in reserpine-induced myalgia rats. Int J Mol Sci. 2017;18(7):1389. doi:10.3390/ijms18071389

 Web of Science ®Google Scholar

Favero G, Bonomini F, Franco C, Rezzani R. Mitochondrial dysfunction in skeletal muscle of a fibromyalgia model: the potential benefits of melatonin. Int J Mol Sci. 2019;20(3):765. doi:10.3390/ijms20030765

 Web of Science ®Google Scholar

Durappanavar PN, Nadoor P, Waghe P, Pavithra BH, Jayaramu GM. Melatonin ameliorates neuropharmacological and neurobiochemical alterations induced by subchronic exposure to arsenic in wistar rats. Biol Trace Elem Res. 2019;190(1):124–139. doi:10.1007/s12011-018-1537-1

 Web of Science ®Google Scholar

Wang YS, Li YY, Cui W, et al. Melatonin attenuates pain hypersensitivity and decreases astrocyte-mediated spinal neuroinflammation in a rat model of oxaliplatin-induced pain. Inflammation. 2017;40(6):2052–2061. doi:10.1007/s10753-017-0645-y

 Web of Science ®Google Scholar

Areti A, Komirishetty P, Akuthota M, Malik RA, Kumar A. Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res. 2017;62(3). doi:10.1111/jpi.12393

 Web of Science ®Google Scholar

Phiphatwatcharaded C, Topark-Ngarm A, Puthongking P, Mahakunakorn P. Anti-inflammatory activities of melatonin derivatives in lipopolysaccharide-stimulated RAW 264.7 cells and antinociceptive effects in mice. Drug Dev Res. 2014;75(4):235–245. doi:10.1002/ddr.2014.75.issue-4

 Web of Science ®Google Scholar

Kumar A, Meena S, Kalonia H, Gupta A, Kumar P. Effect of nitric oxide in protective effect of melatonin against chronic constriction sciatic nerve injury induced neuropathic pain in rats. Indian J Exp Biol. 2011;49(9):664–671.

 Web of Science ®Google Scholar

Zurowski D, Nowak L, Machowska A, Wordliczek J, Thor PJ. Exogenous melatonin abolishes mechanical allodynia but not thermal hyperalgesia in neuropathic pain. The role of the opioid system and benzodiazepine-gabaergic mechanism. J Physiol Pharmacol. 2012;63(6):641–647.

 Web of Science ®Google Scholar

Borsani E, Buffoli B, Bonazza V, Reiter RJ, Rezzani R, Rodella LF. Single administration of melatonin modulates the nitroxidergic system at the peripheral level and reduces thermal nociceptive hypersensitivity in neuropathic rats. Int J Mol Sci. 2017;18(10):2143. doi:10.3390/ijms18102143

 Web of Science ®Google Scholar

Chenaf C, Chapuy E, Libert F, et al. Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence. Pain. 2017;158(1):149–160. doi:10.1097/j.pain.0000000000000738

 Web of Science ®Google Scholar

Chiang RP, Huang CT, Tsai YJ. Melatonin reduces median nerve injury-induced mechanical hypersensitivity via inhibition of microglial p38 mitogen-activated protein kinase activation in rat cuneate nucleus. J Pineal Res. 2013;54(2):232–244. doi:10.1111/jpi.12029

 Web of Science ®Google Scholar

Chen KH, Yang CH, Wallace CG, et al. Combination therapy with extracorporeal shock wave and melatonin markedly attenuated neuropathic pain in rat. Am J Transl Res. 2017;9(10):4593–4606.

 PubMed Web of Science ®Google Scholar

Yang CH, Yip HK, Chen HF, et al. Long-term therapeutic effects of extracorporeal shock wave-assisted melatonin therapy on mononeuropathic pain in rats. Neurochem Res. 2019;44(4):796–810. doi:10.1007/s11064-018-02713-0

 Web of Science ®Google Scholar

Lin JJ, Lin Y, Zhao TZ, et al. Melatonin suppresses neuropathic pain via MT2-dependent and -independent pathways in dorsal root ganglia neurons of mice. Theranostics. 2017;7(7):2015–2032. doi:10.7150/thno.19500

 Web of Science ®Google Scholar

Liu YY, Yin D, Chen L, et al. Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain. Psychopharmacology (Berl). 2014;231(20):3973–3985. doi:10.1007/s00213-014-3530-5

 Web of Science ®Google Scholar