Melanin-concentrating hormone, melanocortin receptors and regulation of luteinizing hormone release

Melanin-concentrating hormone (MCH) is a neuropeiptide, identified by its a bility to either mimic or antagonize the melanin-dispersing action of alpha -melanocyte stimulating hormone (alpha MSH) on skin melanophores. MCH and a lpha MSH also have antagonistic actions in the brain affecting feeding beha viour, aggression, anxiety, arousal and reproductive function through the r elease of luteinizing hormone (LH). It is not clear, however, how they exer t their opposite effects in the central nervous system (CNS). One possibili ty is that they act via a common receptor. In this study we have examined t he effect of a number of MC receptor antagonists, with relative selectivity for the MC3, 4 and 5 subtypes, on the actions of MCH on LH release. We con firmed that bilateral administration of MCH (100 and 200 ng/side) into the medial preoptic area of oestrogen-primed (oestradiol benzoate 5 mu g) ovari ectomized anaesthetized rats, stimulated the release of LH. This effect was blocked by the concomitant administration into the medial preoptic area of the MC4/5 antagonist ([DArg(8)]ACTH(4-10) and the MC3/5 antagonist ([Ala(6 )]ACTH(4-10)-both at 500 ng/side-but not by the MC3/4 antagonist, SHU9119 ( 200 ng/side). Furthermore, the MC3 agonist [Nle(3)]-gamma(2) MSH failed to affect LH release, These results indicate that the MC3 and MC4 receptors ar e not involved in mediating the action of MCH but are consistent with an ac tion via the MC5 subtype. Preputial glands, which express MC5 receptors, we re also stimulated by MCH which is in keeping with this idea. In HEK293 cel ls transfected with the MC5 receptor MCH increased the production of IP3. H owever, it was much less potent than alpha MSH and unlike alpha MSH, had no effect on the production of cAMP. NIGH (10(-10) to 10(-5) M) also failed t o displace (INDP)-N-125-MSH from cells transfected with MC5 receptors indic ating that it was not acting as a competitive antagonist and its binding si te was distinct from that of alpha MSH. Thus while MCH may function as an a gonist at the MC5 receptor, its stimulation of LH release is more likely to be mediated via a specific MCH receptor that has common properties with th e MC5 receptor.