-MSH has potent anti-inflammatory properties but little is known about the specific melanocortin receptors (MC-Rs) that mediate these effects or about the role of the melanocortin system in modulating cytokine responses to an inflammatory challenge in the primate in vivo. We have therefore studied the effects of infusion of the -MSH agonist, NDP-MSH, the -MSH antagonist, SHU9119, and the selective MC3-R agonist, D-Trp8--MSH, compared with saline, on pro-inflammatory cytokine (TNF-, IL-1, IL-6), anti-inflammatory cytokine (IL-10, IL-1ra) and pituitary-adrenal responses to endotoxin in ovariectomized monkeys. In the first study NDP-MSH or SHU9119 was infused iv for 7 h starting at 0800 h; endotoxin was injected at 1000 h and serial blood samples were collected (n = 6). NDP-MSH significantly attenuated pro-inflammatory cytokine responses to endotoxin. The area under the response curve (AUC) decreased by 61% for TNF- (P = 0.02), 47% for IL-1 (P = 0.02) and 41% for IL-6 (P = 0.04); there was no effect on IL-1ra or IL-10. SHU9119 did not affect pro-inflammatory cytokine responses but decreased the IL-10 response by 31% (P = 0.03). NDP-MSH also attenuated ACTH (P < 0.001) and cortisol (P = 0.02) responses. In a second study, effects of D-Trp8--MSH were similarly examined in 7 monkeys. The AUC for IL-6 was decreased by 37% (P = 0.04) by D-Trp8--MSH; the AUC for IL-10 was increased by 22% but this was not significant. However, the ratio of IL-6 to IL-10 was significantly decreased by D-Trp8--MSH (P = 0.04) consistent with a relatively more anti-inflammatory cytokine environment. These results indicate that NDP-MSH can attenuate pro-inflammatory cytokine responses in the primate consistent with prior studies in the rodent and provide new evidence for a role of the MC3-R in this process. Moreover, they show for the first time that SHU9119, a mixed MC3/4-R antagonist, can decrease the IL-10 response, establishing a physiological role for endogenous MSH in modulating the release of an anti-inflammatory cytokine.