Corticotropin (ACTH) and melanotropin (MSH) peptides (melanocortins) are produced not only in the pituitary but also in the brain, with highest concentrations in the arcuate nudeus of the hypothalamus and the commisural nucleus of the solitary tract. We have identified a receptor for MSH and ACTH peptides that is specdflcally expressed in regions of the hypothalamus and limbic system. This melanocortin receptor (MC3-R) is found in neurons of the arcuate nucleus known to express proopiomelanocortin (POMC) and in a subset of the nuclei to which these neurons send projections.The MC3-R is 43% identical to the MSH receptor present in melanocytes and is strongly coupled to adenylyl cyclase. Unlike the MSH or ACTH receptors, MC3-R is potendy activated by 'yMSH peptides, POMC products that were named for their amino acid homology with a-and f-MSH, but lack melanotropic activity. The primary biological role of the yMSH peptides is not yet understood. The location and properties of this receptor provide a pharmacological basis for the action of POMC peptides produced in the brain and possibly a specific physiological role for -MSH.The large proopiomelanocortin (POMC) protein is processed into three main families ofpeptides with adrenocorticotropic, melanotropic, or opiate activities. The melanocortins, which include all POMC peptides except (3-endorphin, are primarily known for their role in the regulation of adrenal steroid production [corticotropin (ACTH)] and pigmentation [a melanotropin (a-MSH)]. In addition to these well-known effects, administration of melanocortin peptides has been reported to increase retention of learned behaviors (1, 2), induce grooming behavior (3), decrease fever (4, 5), stimulate nerve regeneration (6, 7), and increase heart rate, blood pressure, and natriuresis (8, 9). Many ofthese biological activities have been demonstrated to result from direct action of the melanocortin peptides in the brain.Recently, the cloning of the MSH (10, 11) and ACTH receptors (10) (MSH-R and ACTH-R) has provided probes for the examination of MSH-R and ACTH-R mRNA expression. Thus far, MSH-R and ACTH-R mRNA expression has only been detected in melanocytes and in the adrenal cortex, respectively. Although specific high-affinity MSH and ACTH binding has been reported in brain, with highest levels in the hypothalamus (12, 13), no MSH-R or ACTH-R mRNA was detected in the brain by either Northern hybridization or in situ hybridization (14,15). Additionally, melanocortin binding and biological action in the brain display pharmacological profiles that do not match those of either the adrenal The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.ACTH-R or the melanocyte MSH-R. These data suggested the existence of unique melanocortin receptor(s) expressed specifically in the brain.We report here the cloning and characterization of a neural-specific melanocorti...

Although some cultured human melanoma cell lines are responsive to melanotropins (melanocyte-stimulating hormones [MSH]), the prevalence and tissue distribution of MSH receptors in melanoma are unknown. We report here the use of an in situ binding technique to demonstrate specific MSH receptors in surgical specimens of human melanoma. The distribution and binding properties of specific MSH binding sites were determined by autoradiography and image analysis after incubation of frozen tumor tissue sections with a biologically active, radiolabeled analogue of alpha-MSH, [125I]iodo-Nle4, D-Phe7-alpha-MSH ([125I]NDP-MSH). In melanoma specimens from 11 patients, 3 showed high levels of specific binding, 5 showed low levels, and in 3 patients specific binding of [125I]NDP-MSH was not detectable. Specific MSH binding sites were present in melanoma cells, but not in adjacent connective or inflammatory tissues. Melanotropins, including alpha-MSH, NDP-MSH, and ACTH, inhibited [125I]NDP-MSH binding in a concentration-dependent manner, whereas unrelated peptides (somatostatin and substance P) did not. The apparent affinity of alpha-MSH for this binding site was in the nanomolar range (EC50 = 2 X 10(-9) M for inhibition of [125I]NDP-MSH binding in situ), similar to that recently described for the murine melanoma receptor. In one patient, analysis of multiple intratumor samples and tumors excised on three separate occasions revealed high levels of specific MSH binding in all samples. These results suggest that endogenous melanotropins may modulate the activities of human melanoma cells in vivo.

Bacterial infection causes fever, an adaptive but potentially self-destructive response, in the host. Also activated are counterregulatory systems such as the pituitary-adrenal axis. Antipyretic roles have also been postulated for certain endogenous central neuropeptides, including the melanocortins (␣-MSHrelated peptides). To test the hypothesis that endogenous cen- -9119 (168 pmol, i.c.v.) prevented the antipyretic action of exogenous ␣-MSH. In contrast, neither ␣-MSH nor SHU-9119, alone or in combination, affected body temperatures in afebrile rats. In LPS-treated rats, intracerebroventricular injection of SHU-9119 significantly increased fever, whereas intravenous injection of the same dose of SHU-9119 had no effect. Neither intracerebroventricular nor intravenous SHU-9119 significantly affected LPS-stimulated plasma ACTH or corticosterone levels. The results indicate that endogenous central melanocortins exert an antipyretic influence during fever by acting on MCRs located within the brain, independent of any modulation of the activity of the pituitary-adrenal axis.