Role of Melatonin in the Prevention of Morphine-Induced Hyperalgesia and Spinal Glial Activation in Rats: Protein Kinase C Pathway Involved

Purposes: Morphine can induce tolerance and hyperalgesia after long-term administration. Glial activation is believed to cause and maintain a state of morphine-induced pain hypersensitivity. The present study examines the effect of melatonin on tolerance, hyperalgesia, and reactive gliosis induced by morphine in rats. Methods: The study examines the effect of melatonin on morphine-induced hyperalgesia using tail-flick test. Immunohistochemistry and Western blot was performed to investigate the expression of glial fibrillary acidic protein (GFAP) indicative of spinal glial activity. This study also measures protein kinase C (PKC) activity and cyclic adenosine monophosphate (cAMP) levels in spinal cords to investigate the mechanisms which melatonin involved. Results: When coadministered intragastrically (i.g.) with morphine, melatonin in doses of 50 or 100 mg/kg significantly prevented hyperalgesia after termination of morphine. Immunohistochemistry and Western blot with GFAP revealed that melatonin significantly decreased morphine-induced over-expression of GFAP in spinal cord (p < .05). By measuring PKC activity and cAMP levels, the upregulated PKC activity and cAMP levels induced by morphine were significantly inhibited by melatonin. Conclusions: Melatonin can prevent morphine-withdrawal-induced hyperalgesia and glial reactivity. This effect of melatonin after morphine administration may mediated by inhibiting PKC activity and cAMP upregulation.