Melanocortin Receptors and Erectile Function

doi:10.1016/j.eururo.2003.03.001

European Urology

Volume 45, Issue 6, June 2004, Pages 706-713

https://doi.org/10.1016/j.eururo.2003.03.001 Get rights and content

Abstract

Objective: Review the historical and current evidence that suggests that activation of melanocortin receptors modulates erectile activity.

Methods: The available literature was reviewed.

Results: Melanocortin peptides derived from the pro-opiomelanocortin (POMC) precursor protein exert a host of diverse physiological effects in the periphery and in the CNS through interactions with one or more of the five cloned melanocortin receptors. Natural and synthetic melanocortin peptide agonists influence erectile and sexual function in a range of preclinical species. Emerging clinical evidence now suggests that the proerectile effects observed in preclinical species are evident in man as well.

Conclusions: Preclinical and clinical results support the involvement of melanocortins in the modulation of erectile and sexual function. Current evidence indicates that the melanocortin 4 receptor subtype contributes to the proerectile effects observed with pan-receptor agonists. However, the putative receptor subtypes, pathways and mechanisms implicated in mediating the proerectile effects of melanocortins remain to be fully elucidated.

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

References (56)

R.A. Adan et al.
Melanocortins and the brain: from effects via receptors to drug targets
Eur. J. Pharmacol.
(2000)
H. Wessells et al.
Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study
J. Urol.
(1998)
H. Wessells et al.
Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction [In Process Citation]
Urology
(2000)
R.C. Rosen et al.
The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction
Urology
(1997)
J. Lindblom et al.
Autoradiographic discrimination of melanocortin receptors indicates that the MC3 subtype dominates in the medial rat brain
Brain Res.
(1998)
K.E. McKenna
Some proposals regarding the organization of the central nervous system control of penile erection
Neurosci. Biobehav. Rev.
(2000)
I. Gantz et al.
Molecular cloning, expression, and gene localization of a fourth melanocortin receptor
J. Biol. Chem.
(1993)
B.D. Sachs
Contextual approaches to the physiology and classification of erectile function, erectile dysfunction, and sexual arousal
Neurosci Biobehav. Rev.
(2000)
J. Bernabe et al.
Intracavernous pressure changes during reflexive penile erections in the rat
Physiol. Behav.
(1995)
J.E. Wikberg et al.
New aspects on the melanocortins and their receptors
Pharmacol. Res.
(2000)

A.V. Vergoni et al.

Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats

Eur. J. Pharmacol.

(1998)

A. Argiolas et al.

ACTH- and alpha-MSH-induced grooming, stretching, yawning and penile erection in male rats: site of action in the brain and role of melanocortin receptors

Brain Res. Bull.

(2000)

W.J. Martin et al.

Activation of melanocortin MC(4) receptors increases erectile activity in rats ex copula

Eur. J. Pharmacol.

(2002)

H. Mizusawa et al.

alpha-Melanocyte stimulating hormone and oxytocin induced penile erections, and intracavernous pressure increases in the rat

J. Urol.

(2002)

H. Wessells et al.

Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal melanocortin receptors

Neuroscience

(2003)

P. Trivedi et al.

Exploring the site of anorectic action of peripherally administered synthetic melanocortin peptide MT-II in rats

Brain Res.

(2003)

K.W. Horch et al.

A key to the classification of cutaneous mechanoreceptors

J. Invest. Dermatol.

(1977)

J.B. Tatro et al.

Heterogeneity of brain melanocortin receptors suggested by differential ligand binding in situ

Brain Res.

(1994)

L. Marson et al.

Central nervous system innervation of the penis as revealed by the transneuronal transport of pseudorabies virus

Neuroscience

(1993)

F. Giuliano et al.

Central neural regulation of penile erection

Neurosci Biobehav Rev.

(2000)

A. Argiolas

Neuropeptides and sexual behaviour

Neurosci Biobehav Rev.

(1999)

R.A. Adan et al.

Brain melanocortin receptors: from cloning to function

Peptides

(1997)

A. Argiolas et al.

d(CH2)5Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH-(1–24)

Eur. J. Pharmacol.

(1987)

F. Veronneau-Longueville et al.

Oxytocinergic innervation of autonomic nuclei controlling penile erection in the rat

Neuroscience

(1999)

M.R. Melis et al.

Apomorphine-induced penile erection and yawning: site of action in brain

Brain Res.

(1987)

K.K. Chen et al.

Dopaminergic neurotransmission at the paraventricular nucleus of hypothalamus in central regulation of penile erection in the rat

J. Urol.

(1999)

A. Argiolas et al.

Paraventricular nucleus lesion prevents yawning and penile erection induced by apomorphine and oxytocin but not by ACTH in rats

Brain Res.

(1987)

H.B. Schioth et al.

Pharmacological comparison of rat and human melanocortin 3 and 4 receptors in vitro

Regul. Pept.

(2002)

Cited by (65)

Neuropeptides and central control of sexual behaviour from the past to the present: A review
2013, Progress in Neurobiology
Citation Excerpt :
These studies support a major role of MC4 receptors versus MC3 receptors as responsible for the pro-erectile effect of ACTH–MSH derived peptides. Accordingly THIQ, a non-peptide MC4 receptor agonist with >1000-fold selectivity for MC4 receptors compared to MC3 receptors (Van der Ploeg et al., 2002) induces penile erection and increase intracavernous pressure in male rats when given systemically (Martin et al., 2002; Martin and McIntyre, 2004). The stimulation of the cavernous nerves in MC4 wild-type and MC4 receptor knockout mice in the presence or absence of systemic THIQ given intravenously produced a significant augmentation of erectile activity in wild-type mice while no change was seen in MC4 receptor knockout mice (Van der Ploeg et al., 2002).
Of the numerous neuropeptides identified in the central nervous system, only a few are involved in the control of sexual behaviour. Among these, the most studied are oxytocin, adrenocorticotropin, α-melanocyte stimulating hormone and opioid peptides. While opioid peptides inhibit sexual performance, the others facilitate sexual behaviour in most of the species studied so far (rats, mice, monkeys and humans). However, evidence for a sexual role of gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin and galanin-like peptide, cholecystokinin, substance P, vasoactive intestinal peptide, vasopressin, angiotensin II, hypocretins/orexins and VGF-derived peptides are also available. Corticotropin releasing factor, neuropeptide Y, cholecystokinin, vasopressin and angiotensin II inhibit, while substance P, vasoactive intestinal peptide, hypocretins/orexins and some VGF-derived peptide facilitate sexual behaviour. Neuropeptides influence sexual behaviour by acting mainly in the hypothalamic nuclei (i.e., lateral hypothalamus, paraventricular nucleus, ventromedial nucleus, arcuate nucleus), in the medial preoptic area and in the spinal cord. However, it is often unclear whether neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behaviour, except in a few cases (e.g., opioid peptides and oxytocin). Unfortunately, scarce information has been added in the last 15 years on the neural mechanisms by which neuropeptides influence sexual behaviour, most studied neuropeptides apart. This may be due to a decreased interest of researchers on neuropeptides and sexual behaviour or on sexual behaviour in general. Such a decrease may be related to the discovery of orally effective, locally acting type V phosphodiesterase inhibitors for the therapy of erectile dysfunction.
The role of genital nerve afferents in the physiology of the sexual response and pelvic floor function
2011, Journal of Sexual Medicine
Citation Excerpt :
Penile afferents transmit these excitatory oscillating nerve impulses to the spinal cord and higher centers, such as the thalamus [35], which will be discussed later. Melanocortin receptor-4 (MCR4) has been detected close to PN mechanoreceptors [36]. MCR4 is expressed in the rat and human penis, rat spinal cord, hypothalamus, brainstem, and pelvic ganglion.
Our understanding of genital and pelvic floor physiology is rapidly expanding. Penile erection is a neurovascular event controlled by spinal autonomic centers, the activity of which is dependent on input from supraspinal centers and the genitalia. Genital afferent stimulation excites spinal autonomic nuclei and supraspinal sexual centers of both genders.
To present a detailed understanding of the functional importance of genital afferent neuroanatomy and neurophysiology.
English-written articles of diverse disciplines from 1980 to 2010 that contained information on genital anatomy, pudendal/dorsal/perineal/cavernous nerves, vibratory stimulation, reflexogenic erection, peripheral/central nervous system-mediated erectile and micturition pathways, and sexual arousal in animals and humans were reviewed.
Analysis of supporting evidence for the role of genital afferents in the physiology of erectile response and pelvic floor function.
Basic science and clinical studies support the concept that pudendal nerve circuitry serves an essential purpose for sexual behavior, erectile function, penile rigidity, ejaculation, and micturition. Males and females share a comparable pattern of genital afferent neuroanatomy and neurophysiology, and sexual and micturition reflexes are similar in both genders. Pudendal nerve branches communicate with the cavernous nerves and are nitric oxide synthase positive. Genital afferents activate multiple spinal reflexes that modulate erection and micturition. Genital sensory information is transmitted to supraspinal centers important for sexual function.
There is expanding support for the critical role of genital afferent neurophysiology in the mechanisms of erectile function and micturition. Genital afferent stimulation is a safe and natural modality that can be harnessed to amplify autonomic and somatic activity within the penis, female genitalia, spinal cord, and higher centers via established neurological principles. Such physiological adaptive processes may be beneficial in improving sexual response, erectile function, and micturition in many disease states, including in men after radical pelvic surgery. Well-designed and -executed studies in each specific population are needed to authenticate such prospects. Tajkarimi K and Burnett AL. The role of genital nerve afferents in the physiology of the sexual response and pelvic floor function.
Discovery of a piperazine urea based compound as a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist
2011, Bioorganic and Medicinal Chemistry Letters
Melanocortin receptors and their accessory proteins
2011, Molecular and Cellular Endocrinology
Citation Excerpt :
The MC4R is expressed in brain, autonomic nervous system and spinal cord (Gantz et al., 1993b; Mountjoy and Wild, 1998). The MC4R has been found to be involved in erectile dysfunction (Martin and MacIntyre, 2004) and pain (Starowicz and Przewlocka, 2003). Most importantly extensive studies have shown that MC4R is involved in controlling food intake and energy expenditure.
The melanocortin receptor family consists of 5 members which belong to the GPCR superfamily. Their specific ligands, the melanocortins are peptide hormones which are formed by the proteolytic cleavage of the proopiomelanocortin (POMC) protein. It is now recognised that certain GPCRs require accessory proteins for their function. Like these GPCRs the melanocortin receptor family is also known to be associated with accessory proteins that regulate their function.
In this review we will summarise the accessory proteins involved in the function of the 5 melanocortin receptors and in particular focus on the melanocortin 2 receptor accessory protein (MRAP) which is crucial for the function of the MC2R.
Optimization of privileged structures for selective and potent melanocortin subtype-4 receptor ligands
2010, Bioorganic and Medicinal Chemistry Letters
Discovery of a spiroindane based compound as a potent, selective, orally bioavailable melanocortin subtype-4 receptor agonist
2010, Bioorganic and Medicinal Chemistry Letters

View all citing articles on Scopus

View full text

ReviewMelanocortin Receptors and Erectile Function

Abstract

Introduction

Section snippets

Human clinical studies with pan-melanocortin agonists

Melanocortin-induced erectogenesis in preclinical species

Receptor subtype

Sites of action

Mechanisms of melanocortin receptor-mediated erectogenesis

Summary and conclusion

Eur. J. Pharmacol.

J. Urol.

Urology

Urology

Brain Res.

Neurosci. Biobehav. Rev.

J. Biol. Chem.

Neurosci Biobehav. Rev.

Physiol. Behav.

Pharmacol. Res.

Eur. J. Pharmacol.

Brain Res. Bull.

Eur. J. Pharmacol.

J. Urol.

Neuroscience

Brain Res.

J. Invest. Dermatol.

Brain Res.

Neuroscience

Neurosci Biobehav Rev.

Neurosci Biobehav Rev.

Peptides

Eur. J. Pharmacol.

Neuroscience

Brain Res.

J. Urol.

Brain Res.

Regul. Pept.

Review
Melanocortin Receptors and Erectile Function