AC-NLE-c[ASP-HIS-DPHE-ARG-TRP-LYS]-NH 2 INDUCES PENILE ERECTION VIA BRAIN AND SPINAL MELANOCORTIN RECEPTORS H. WESSELLS, a * V. J. HRUBY, c J. HACKETT, a G. HAN, c P. BALSE-SRINIVASAN c AND T. W. VANDERAH b a Department of Urology, University of Washington School of Medicine, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98195, USA b Departments of Anesthesiology and Pharmacology, University of Ar- izona College of Medicine, Tucson, Arizona 85724, USA c Department of Chemistry, University of Arizona, Tucson, Arizona 85724, USA Abstract—Penile erection induced by -melanocyte-stimulat- ing hormone and melanocortin receptors (MC-R) in areas of the spinal cord and periphery has not been demonstrated. To elucidate sites of the proerectile action of melanocortin pep- tides, in awake male rats we administered the MC-R agonist Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 (MT-II) i.c.v., intra- thecal (i.th.) and i.v. and scored penile erection and yawning. Injection of the MC-R antagonist Ac-Nle-c[Asp-His-DNal(2')- Arg-Trp-Lys]-NH 2 (SHU-9119) i.c.v. or i.th. in combination with i.th. MT-II differentiated spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intra- cavernous pressure responses to intracavernosal injection of MT-II in the anesthetized rat. I.c.v., i.th., and i.v. MT-II induced penile erections in a dose-dependent fashion. Yawning was observed with i.c.v. and i.v. MT-II, while spinal injection did not produce this behavior. Intrathecal delivery of MT-II to the lumbosacral spi- nal cord was more efficacious in inducing erections than i.c.v. or i.v. administration; SHU-9119 blocked the erectile responses to i.th. MT-II when injected i.th. but not i.c.v. Intra- cavernosal MT-II neither increased intracavernous pressure nor augmented neurostimulated erectile responses. We confirmed the central proerectile activity of MT-II and demonstrated that in addition to a site of action in the brain, the distal spinal cord contains melanocortin receptors that can initiate penile erection independent of higher centers. These results provide new insight into the central melano- cortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction. © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. Key words: MSH, MT-II, SHU-9119, spinal cord, rats, sex be- havior. The CNS is the primary control center for sexual motivation and penile erection (Giuliano and Rampin, 2000; Anders- son, 2001). Stimulation of dopamine receptors in the re- gion of the paraventricular nucleus (PVN) of the hypothal- amus induces penile erection by releasing oxytocin to extrahypothalamic areas (Benassi-Benelli et al., 1979; Ar- giolas et al., 1988). This action is mediated by nitric oxide (Melis et al., 1996). The hypothalamus contributes de- scending oxytocinergic fibers to the spinal cord (Buijs et al., 1978), and the paraventriculospinal tract originates in the parvocellular part of the PVN (Hosoya and Matsushita, 1979). Specific oxytocin binding sites are present in the sacral parasympathetic nucleus (Veronneau-Longueville et al., 1999), which, via the pelvic and cavernous nerves, projects proerectile autonomic efferents to the corpus cav- ernosum. Other neuropeptides implicated in penile erec- tion and sex behavior in animals include neurokinins, lu- teinizing hormone-releasing hormone fragments, proopio- melanocortin (POMC), and melanocortins (Dornan et al., 1993; Hughes et al., 1988; Medina et al., 1998). The melanocortin peptides -,-, and -melanocyte- stimulating hormone (MSH) and adrenocorticotrophic hor- mone (ACTH), derived by post-translational processing of the POMC gene product, and melanocortin receptors me- diate important physiological functions including food in- take, penile erection, sexual motivation, immune function and grooming (Meyerson and Bohus, 1976; Fan et al., 1997; van der Kraan et al., 1998; Vergoni et al., 1998; Haskell-Luevano et al., 2000; Wikberg et al., 2000; Mac- Neil et al., 2002). Central administration of -MSH and ACTH in rats induces penile erection due to an action in the regions surrounding the third ventricle (Argiolas et al., 1988). The specific hypothalamic nuclei in which -MSH acts to produce penile erection include the PVN, dorsome- dial nucleus, ventromedial nucleus, and anterior hypotha- lamic area (Argiolas et al., 2000). Antagonists of oxytocin or dopamine receptors do not block the erectogenic activity of -MSH (Bertolini and Gessa 1981; Mizusawa et al., 2002). Of the five G-protein-coupled melanocortin recep- tors (MC-R), only MC 3 and MC 4 receptors are expressed in the nervous system; the relative contribution of each to melanocortin-induced erection is unclear. Vergoni et al. (1998) showed that the selective MC 4 receptor antagonist HS014 does not impair erectile responses to -MSH when administered i.c.v. However, Van der Ploeg et al. (2002) used pharmacological and genetic tools to demonstrate that the MC 4 receptor modulates reflexogenic, copulatory and neurostimulated erections. Although spinal -MSH did not induce erections in a recent study in the rat (Mizusawa et al., 2002), dopamine and oxytocin exert proerectile ac- *Corresponding author. Tel: +1-206-731-3205; fax: +1-206-731- 4709. E-mail address: wessells@u.washington.edu (H. Wessells). Abbreviations: ACTH, adrenocorticotrophic hormone; ANOVA, analy- sis of variance; BP, blood pressure; ICP, intracavernous pressure; i.th., intrathecal; MC-R, melanocortin receptor; MSH, melanocyte-stim- ulating hormone; MT-II, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 ; POMC, proopiomelanocortin; PVN, paraventricular nucleus; RP-HPLC, reverse-phase high-performance liquid chromatography; SHU-9119, Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH 2 . Neuroscience 118 (2003) 755–762 0306-4522/03$30.00+0.00 © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-4522(02)00866-7 755