alpha-MSH and gamma-MSH inhibit IL-1beta induced activation of the hypothalamic-pituitary-adrenal axis through central melanocortin receptors.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuroimmunomodulatory peptide that is involved in the control of host responses trough modulation of production and action of proinflammatory cytokines in inflammatory cells in the periphery and within the central nervous system (CNS). However, little is known about the receptors that mediate the modulatory effects of alpha-MSH in the CNS. The objective of the present study was to establish the specific melanocortin receptors involved in the inhibition by MSH peptides of IL-1beta-induced activation of the HPA. i.c.v. injection of 12.5 ng of IL-1beta caused significant changes in plasma corticosterone, as compared to basal levels. The treatment with gamma-MSH (1 microg), an MC3 receptor agonist, resulted in significant reduction of the IL-1beta-induced plasma corticosterone levels. Administration of the MC3/MC4 receptor antagonist SHU9119 blocked this effect. Besides, treatment with a high dose of alpha-MSH (1 microg) increased plasma corticosterone. When alpha-MSH was given at a lower dose (0.1 microg), it did not modify corticosterone levels but caused an inhibitory effect on the corticosterone release induced by IL-1beta. The administration of SHU9119 or a more selective MC4 receptor antagonist like HS014 blocked the effects of alpha-MSH. In conclusion, our results suggest that both alpha-MSH and gamma-MSH are capable of inhibiting the effect of the IL-1beta on the activation of HPA axis acting at the CNS, and that this effect is mediated by specific central melanocortin receptors.