Melanocortins (alphaMSH and ACTH-related peptides) influence the physiological functions of certain peripheral organs, including exocrine and endocrine glands. This study was designed to determine the identity and anatomical localization of the melanocortin receptors (MC-R) expressed in these organs in the rat. MC5-R messenger RNA was found in exocrine glands, including lacrimal, Harderian, preputial, and prostate glands and pancreas, as well as in adrenal gland, esophagus, and thymus, as demonstrated by ribonuclease protection assays. In exocrine glands, MC5-R messenger RNA expression was restricted to secretory epithelia. MC-R protein was likewise present in secretory epithelia of exocrine glands, as determined by 125I-labeled [Nle4,D-Phe7]alphaMSH ([125I]NDP-MSH) binding and autoradiography in tissue sections. Specific [125I]NDP-MSH binding was also observed in adrenal cortex, thymus, spleen, and esophageal and trachealis muscle. MC receptors in these sites are accessible to circulating MC-R agonists in vivo, as specific binding of [125I]NDP-MSH was observed in exocrine and adrenal glands after systemic injection in vivo. Taken together, these findings show that the MC5 receptor is commonly and selectively expressed in exocrine glands and other peripheral organs. Based on these findings and compelling evidence from other studies, a functional coherence is suggested between central and peripheral actions of melanocortins and melanocortin receptors in physiological functions, including thermoregulation, immunomodulation, and sexual behavior.

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Melanocortins (MC), neuropeptides derived from pro-opiomelanocortin, have been implicated in enhancing neurite outgrowth via an as yet unknown mechanism. Recently, five MC receptors have been identified, three of which, the MC3-R, the MC4-R and the MCs-R, are expressed in the nervous system. In this study, a-MSH and the melanocortin analog [D-PheT]ACTH (4-10) were able to stimulate neurite outgrowth in the neuroblastoma cell line Neuro 2A. ACTH (4-10), -/2-MSH and ORG2766 were inactive. In addition, the MCa-R antagonist [D-Arg8]ACTH (4-10), inhibited the a-MSH effect, indicating that the MCa-R mediated stimulation of neurite outgrowth by o~-MSH. Indeed, the presence of MCa-R mRNA in Neuro 2A cells was demonstrated by a RNase protection assay. Heterologous expression of the MCs-R in Neuro 2A cells lead to the recruitment of a responsiveness to -/2-MSH, but did not increase the effect of a-MSH on neurite outgrowth. This finding indicated that the function of MC4-R can also be exerted by another MC receptor, suggesting that the coupling to G,, which they have in common, plays an essential role in the neurite outgrowth promoting effect. This was further substantiated by the fact that forskolin treatment per se induced neurite outgrowth in a similar fashion. These data imply that the neurotrophic properties of a-MSH are likely to result from G~-coupled MC receptor activity in neuronal cells.