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Massimo Beltramo"The role of melanocortin system in nociception; a pharmacological and expression analysis"

Abstract :

Pain is one of the most common reasons for seeking medical attention, and neuropathic pain is among the most common types of pain. Despite its prevalence, neuropathic pain is often under recognized and inadequately treated. Given the limitations of the available pharmacotherapeutic options to treat neuropathic pain, a considerable number of patients may experience only moderate improvements of their symptoms.
In order to discover better therapeutics for chronic pain a significant number of biological targets were evaluated for their potential utility in pain treatment. Amongst the wide range of modulators studied, the melanocortin (MC) system represents a relatively new, intriguing, potential target for pain control. The melanocortins were first identified based on the activity elicited by pituitary extract on frog skin pigmentation assay. Additional physiological functions were identified later and the complexity of the melanocortin system unveiled. Up to date five different receptors (MC1-5), several endogenous agonists (aMSH, ßMSH, ACTH, etc) and two endogenous antagonists (agouti and agouti related protein) have been described.
To further investigate the implication of MC system in chronic pain, we have used a double approach. From one side we have performed in vivo studies on the effects of several MC antagonists on animal models of persistent pain (spinal nerve ligation, chronic constriction injury and formalin). On the other hand we used immunocytochemical analysis and gene expression study to corroborate our in vivo finding. Our finding that the endogenous antagonist agouti related protein is present in key areas of the pain pathway suggests the hypothesis that the endogenous melanocortin system could modulate pain perception not only positively but also negatively. The antinociceptive effect induced by in vivo administration of the agouti related protein lends further support to this hypothesis. The experimental evidence gathered, together with the published data, suggest that MC analgesia is primary mediated by the MC 4 receptors. The development of non-peptidic selective MC4 receptor antagonists would be an essential step to further assess the analgesic profile and therapeutic interest of the MC system.          

Marc Landry