Control of Penile Erection by the Melanocortinergic System: Experimental Evidences and Therapeutic Perspectives

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…This compound has strong binding to MC receptors 1, 3, and 4, with a higher affinity for the MC4 receptor over MC3, where it acts as an agonist (Giuliano, 2004;King et al, 2007).…”

“…However, it is well established that the balance between contractant and relaxant factors controls the degree of tone of the penile vasculature and of the smooth muscle of the corpora cavernosa (CC) and determines the functional state of the penis: detumescence and flaccidity, tumescence and erection. Several pharmacological, physiological, and clinical aspects of erectile function and dysfunction have been reviewed previously (e.g., Andersson and Wagner, 1995;Argiolas and Melis, 1995, 2004, 2005Giuliano andRampin, 2000, 2004;, but the field expands continuously and has been subject to several recent reviews (Baskerville and Douglas, 2008;Burnett et al, 2010;Gratzke et al, 2010a;Melis and Argiolas, 2011). The present review is an attempt to update the rapidly expanding information on some of the transmit-1 Abbreviations: ␣-MSH, ␣-melanocyte-stimulating hormone; ABT-724, 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole); ACE, angiotensin-converting enzyme; ACh, acetylcholine; AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide; AM630, 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl-(4-methoxyphenyl)methanone; AMPA, amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid; Ang II, angiotensin II; ANP, atrial natriuretic peptide; AR, adrenergic receptor; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide; cAK, protein kinase A; CB, cannabinoid; CC, corpora cavernosa; cGK, cGMP-dependent protein kinase; CGRP, calcitonin gene-related peptide; CNP, C-type natriuretic peptide; CNS, central nervous system; CV, cardiovascular; ED, erectile dysfunction; eNOS, endothelial nitric-oxide synthase; ET, endothelin; GC, guanylyl cyclase; HO, heme oxygenase; 5-HT, 5-hydroxytryptamine; ICP, intracavernosal pressure; IPA, internal pudendal artery; IP 3 , inositol 1,4,5-trisphosphate; L-NAME, N G -nitro-L-arginine methyl ester; MC, melanocortin; m-CCP, m-chlorophenylpiperazine; MK-801, dizocilpine maleate; MLC, regulatory light-chain subunits of myosin; MLCK, myosin light-chain kinase; MPOA, medial preoptic area; MT-II, melanotan-II; NA, noradrenaline; NANC, nonadrenergic, noncholinergic; NMDA, N-methyl-D-aspartic acid; nNOS, neuronal nitric-oxide synthase; NOS, nitric-oxide synthase; PACAP, pituitary adenylate cyclase-activating polypeptide; PDE, phosphodiesterase; PG, prostaglandin; pGC, particulate GC; PKC, protein kinase C; PKG, protein kinase G; PVN, paraventricular nucleus; R 141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride; RAS, renin-angiotensin system; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; SHU-9119, Ac-Nlecyclo(Asp-His-D-2-Nal-Arg-Trp-Lys)-NH; SIN-1, 3-morpholinosydnonimin hydrochloride (linsidomine); SM, smooth muscle; SNP, sodium nitroprusside; TNF, tumor necrosis factor; 304,VIP,vasoactive intestinal peptide;VPAC,VIP receptor;…”

Preclinical effects of melanocortins in male sexual dysfunction

“…26 It has been proposed that melanocortins, oxytocin and dopamine use a common pathway in the CNS that involves activation of NO to control erection. 27 Five melanocortin receptors have been identified that are associated with such diverse biological functions as skin pigmentation, food intake, the sleep-wake cycle and sexual response. Investigations into the role of the melanocortin system on sexual response has focused on the melanocortin 3 (MC3R) and melanocortin 4 (MC4R) receptors in the CNS.…”

“…There is abundant expression of both MC3R and MC4R in the brain and in peripheral genital sensory outputs (Figure 2). 27 However, MC4R has been shown to modulate erectile function and sexual behavior, whereas MC3R has not been shown to have a pro-erectile effect. 28 MC4R is expressed in the rat and human penis, as well as in rat spinal cord, hypothalamus, brainstem and pelvic ganglion, but not in rat corpus cavernosal smooth muscle cells.…”

Centrally acting drugs for erectile dysfunction: Do they have a future?

“…Adrenocorticotropic hormone (ACTH) and α-melanocyte stimulating hormone (α-MSH) are melanocortin peptides that can induce penile erection in animals after intra-or periventricular administration [31,32]. Because erections in response to intracerebroventricular administration of ACTH were not attenuated by lesions of the PVN, other mechanisms than those involving dopaminergic erectile signals may be considered for ACTH [16].…”