EVALUATION OF THE ROLE OF MELATONIN IN FORMALIN-INDUCED PAIN RESPONSE IN MICE

Background: Melatonin, the major secretory product of pineal gland has been suggested to play a regulatory role in the circadian rhythm of body activities including the pain sensitivity. Three subtypes of melatonin receptors, i.e. ML1, ML2 and ML3 have been identified. AIM: To investigate the antinociceptive activity of melatonin and to unravel the underlying receptor mechanisms involved in this action. MATERIAL AND METHODS: Effect of melatonin (25-100 mg/kg, ip) and its interaction with putative melatonin receptor antagonists and opioidergic and serotoninergic agents have been studied in formalin test, a model of tonic continuous pain. Formalin (0.1 ml of 1% solution) was injected under the plantar surface of right hind paw of mice and the time an animal spent in licking the injected paw was measured. STATISTICAL ANALYSIS: The data were analysed by one-way ANOVA followed by Tukey's test for multiple comparisons. RESULTS: Injection of formalin produced two phases of intense licking, an early phase (0-5 min) and a late phase (20-25 min). Melatonin dose-dependently decreased the licking response in both the phases, effect being more marked in the late phase. Luzindole, a ML₁ receptor antagonist did not block but rather enhanced the antinociceptive activity of melatonin. However, prazosin, a ML₂ receptor antagonist in the low dose (0.5 mg/kg) significantly attenuated but in higher dose (1 mg/kg) enhanced the analgesic effect of melatonin. Naloxone, an opioid receptor antagonist did not reverse but morphine, an opioid agonist enhanced the antinociceptive activity of melatonin. Both mianserin and ondansetron the 5HT₂ and 5HT₃ receptor antagonists, respectively increased the analgesic effect of melatonin. CONCLUSION: The present results suggest the involvement of ML₂ receptors in mediating the antinociceptive activity of melatonin in formalin-induced pain response. Further an interplay between melatonin, alpha-1 adrenergic and 5HT₂ and 5HT₃ serotoninergic receptors may also be participating in this action.

Keywords
Melatonin, formalin test, antinociceptive activity, melatonin receptor antagonists, opioidergic agents, serotoninergic agents