ReviewMelanocortin Receptors and Erectile Function
Introduction
In the 1950s and 1960s, Ferrari and colleagues showed that direct central administration of alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH) induce sexual excitement in a range of experimental species including dogs, rabbits, monkeys, and cats (see [1] for review). Over the ensuing decades, investigators determined that alpha-MSH and ACTH derive from the pro-opiomelanocortin (POMC) gene and that the behavioral effects of these peptides are attributable to actions at one or more of the five cloned melanocortin receptors (MC1-5R; see Table 1) [2]. However, the link between proerectile activity in preclinical species and erectogenesis in man emerged only after dermatologist Norman Levine noted that men receiving an experimental medicine designed to cause tanning (Melanotan II or MT-II) presented with unexpected erections [3]. The observation of enhanced erectile activity led to the formal study of MT-II in men with erectile dysfunction.
Section snippets
Human clinical studies with pan-melanocortin agonists
MT-II, a cyclic peptide analog of alpha-MSH, exhibits agonist activity at 4 of the 5 known melanocortin receptors, namely MC1R, MC3R, MC4R and MC5R (Table 1) [4]. In a double-blind crossover study, Wessells and colleagues demonstrated that, compared to placebo controls, subcutaneous administration of MT-II significantly increased the number of erectile events in men with psychogenic erectile dysfunction (ED) [5]. Erectile activity was quantitated by measuring RigiScan activity. Eight of ten men
Melanocortin-induced erectogenesis in preclinical species
In one of the first systematic investigations of the mechanisms that underlie melanocortin-induced erectogenesis, Ferrari and colleagues demonstrated that intracerebroventricular injections of ACTH-like peptides caused yawning, stretching and penile erections in rabbits [10]. These investigators dissociated the effects of the melanocortin peptides on penile erection and stretching/yawning and further showed that these proerectile effects were mediated by cAMP, were specific for ACTH and
Receptor subtype
Since ACTH, alpha-MSH, MT-II and PT-141 do not discriminate amongst MC1R, MC3R, MC4R and MC5R, the melanocortin receptor subtype(s) through which these peptides produce erectogenic effects is unknown. Only MC3R and MC4R are expressed in regions known to participate in the modulation of erectile function [11], [12], [13]. In anesthetized rabbits, SHU 9119, an antagonist to MC3R and MC4R, abolished MT-II-induced increases in intracavernosal pressure [14]. To further distinguish the contribution
Sites of action
The unique profile of melanocortin-induced erectogenesis suggests that the sites of action may be distinct from other centrally and peripherally acting erectogenic agents. The generation and modulation of penile erection requires the integration of information of peripheral, supraspinal and spinal origin. Receptor localization studies and targeted pharmacological approaches indicate that melanocortin receptors in the periphery as well as in the brain and spinal cord likely contribute to the
Mechanisms of melanocortin receptor-mediated erectogenesis
The ability of MCR agonists to modulate erectile activity at peripheral, supraspinal and spinal levels raises several questions with respect to potential interactions of this receptor system with the biochemical and pharmacological pathways that control erectile activity. For example, we know that peripherally-acting agents such as sildenafil (as well as vardenafil and tadalafil) enhance erectile function by modulating the nitric oxide (NO)-cGMP pathway [39] and that neuronal nitric oxide
Summary and conclusion
The pan-melanocortin receptor agonists, MT-II and PT-141, augment erectile activity in men with and without erectile dysfunction. These clinical findings are consistent with the proerectile effects of melanocortins in animals. While many questions remain with respect to sites and mechanisms of action of melanocortin agonists, the evidence reviewed herein favors the hypothesis that activation of melanocortin receptors in the periphery, in the brain and in the spinal cord participate in the
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