Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.