Melanocortins are a group of small protein molecules that share the same precursor molecule, POMC (proopiomelanocortin). (25) These peptides include ACTH (adrenocorticotropic hormone), the melanocyte-stimulating hormones ([alpha]-MSH, [beta]-MSH and [gamma]-MSH), [beta]- and [gamma]-lipotropin, and [beta]-endorphin. In the CNS, melanocortins may act as neurohormones or neurotransmitters, regulating numerous functions within the neuronal systems in which they are synthesized and secreted. (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. (2
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. In mice, administration of an MC4R agonist increased copulation, whereas knockout mice lacking the gene encoding for the receptor showed decreased copulatory behavior.
Melanocortins and erection
Preclinical work conducted indicate that melanocortins promote erection primarily through activity in the CNS. Both ACTH and [alpha]-MSH injected into the hypothalamic periventricular region of the third ventricle of male rats resulted in increased levels of penile erection, as well as stretching, yawning and grooming. (29) However, neither caused those effects when injected into the preoptic area, the caudate nucleus or the CA1 field of the hippocampus.
In a different rat model, 10 min after intracerebroventricular administration of [alpha]-MSH, there was a 10-fold increase in the frequency of penile erections. (30) Increases in erection frequencies were seen by injecting both ACTH and [alpha]-MSH directly into PVN of the hypothalamus. Blocking the MC4R with HS014, a non-selective MC4R antagonist, did not alter these responses...