Antagonism of the melanocortin system reduces cold and mechanical allodynia in mononeuropathic rats

The presence of both pro-opiomelanocortin-derived peptides and melanocortin (MC) receptors in nociception-associated areas in the spinal cord suggests that, at the spinal level, the MC system might be involved in nociceptive transmission. In the present study, we demonstrate that a chronic constrict ion injury (CCI) to the rat sciatic nerve, a lesion that produces neuropath ic pain, results in changes in the spinal cord MC system, as shown by an in creased binding of I-125-NDP-MSH to the dorsal horn. Furthermore, we invest igated whether intrathecal administration (in the cisterna magna) of select ive MC receptor ligands can affect the mechanical and cold allodynia associ ated with the CCI. Mechanical and cold allodynia were assessed by measuring withdrawal responses of the affected limb to von Frey filaments and withdr awal latencies upon immersion in a 4.5 degreesC water bath, respectively. W e show that treatment with the MC receptor antagonist SHU9119 has a profoun d anti-allodynic effect, suggesting that the endogenous MC system has a ton ic effect on nociception. In contrast, administration of the MC4 receptor a gonists MTII and D-Tyr-MTII primarily increases the sensitivity to mechanic al and cold stimulation. No antinociceptive action was observed after admin istration of the selective MC3 receptor agonist Nle-gamma -MSH. Together, o ur data suggest that the spinal cord MC system is involved in neuropathic p ain and that the effects of MC receptor ligands on the responses to painful stimuli are exerted through the MC4 receptor. In conclusion, antagonism of the spinal melanocortin system might provide a new approach in the treatme nt of neuropathic pain.