A role for the melanocortin 4 receptor in sexual function

Abstract
By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings]
Five melanocortin heterotrimeric GTP-binding protein (G protein)-coupled receptors have been identified as expressed in different tissues. The functional role of each of these five melanocortin receptors is being defined. Rodent and human genetic and pharmacological evidence indicates that activation of melanocortin 4 receptor (MC4R) results in a lean phenotype, whereas inactivation of the MC4R results in obesity. Recent studies have demonstrated that MTII, a cyclic analogue of ?-melanocyte stimulating hormone (?-MSH) and a subnanomolar agonist of the MC1R, MC3R, MC4R, and MC5R can stimulate intermittent penile erections in man. The receptor(s) responsible for the proerectile activity of MTII have not been defined. In the rat, the induction of grooming behavior by melanocortin agonists may also be related to sexual function. Intracerebroventricular injections of other melanocortin receptor agonists such as adrenocorticotropin (ACTH) and ?-MSH induce episodes of stretching, yawning, and penile erection in rats. These behaviors are reproduced by microinjections of ACTH and ?-MSH into specific hypothalamic regions, including the paraventricular nucleus. MC4R expressed in the hypothalamus could mediate the erectogenic effects of ?-MSH and its analogues. This notion is challenged by the finding that injection of a putative MC4R-specific antagonist, HS014, into the hypothalamus failed to block ?-MSH-induced penile erections at doses that inhibited stretching and yawning. Differential MC4R antagonist receptor occupancy at which stretching and yawning or penile erection can be blocked could provide an alternative explanation for these observations. We used pharmacological and genetic tools to unravel the melanocortin receptor involvement in erectile function and to characterize the mechanism(s) by which melanocortin receptors (MCRs) modulate sexual function.

PT-141]Melanotan-II:* binds to MC1R, MC3R, MC4R & MC5R