Activation of melanocortin MC4 receptors increases erectile activity in rats ex copula

Abstract Melanocortin peptide agonists, α-melanocyte stimulating hormone (α-MSH) and melanotan-II, stimulate erectile activity in a variety of species, including man. Since neither peptide discriminates amongst melanocortin receptors, it is not clear which subtype mediates these pro-erectile effects. Here, we present data that melanocortin-induced erectogenesis is mediated by melanocortin MC 4 receptors. Systemic administration of a melanocortin MC 4 receptor agonist ( N -[(3 R )-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1 R )-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1 H -1,2,4-triazol-1ylmethyl)piperidin-1-yl]-2-oxoethylamine; THIQ) with high selectivity over other melanocortin receptors enhanced intracavernosal pressure and stimulated erectile activity in rats ex copula . THIQ dose-dependently (1–5 mg/kg, i.v.) increased the total number of erections, to an extent comparable or greater than that produced by apomorphine (0.025 mg/kg, s.c.). Central administration of THIQ (20 μg, intracerebroventricular (i.c.v.)) increased the number of reflexive penile erections; whereas administration of both a nonselective endogenous melanocortin MC 4 receptor antagonist (agouti-related protein (AgRP), 5.5. μg, i.c.v.) and a melanocortin MC 4 receptor preferring antagonist (MPB10, 1 mg/kg, i.v.) blocked THIQ-induced erectogenesis. These pro-erectile effects were also attenuated by systemic or central administration of an oxytocin antagonist (L-368899, 1 mg/kg, i.v.). Thus, melanocortin MC 4 receptor activation is sufficient for erectogenesis and these effects may involve oxytocinergic pathways.