The proopiomelanocortin (POMC)-derived peptides are important regulators in a number of central nervous system pathways especially as they relate to food intake as well as metabolic and autonomic responses. In this study, we investigated the sympathetic nervous and cardiovascular responses to intracerebroventricular (i.c.v.) administration of alpha melanocyte stimulating hormone (alphaMSH), beta-endorphin (beta-END) and adrenal corticotrophic hormone (ACTH) alone or in the presence of a melanocortin antagonist, or an opioid antagonist, in normal animals. The i.c.v. administration of alphaMSH and ACTH resulted in a significant increase in the lumbar sympathetic nerve activity (LSNA) that was accompanied by an increase in mean arterial pressure (MAP). On the other hand i.c.v. administration of beta-END decreased the LSNA and MAP. The pretreatment of animals with the melanocortin-4 (MC-4) receptor antagonist, agouti protein, significantly antagonized the response to alphaMSH and also, paradoxically, not only antagonized the response to beta-END but converted its inhibitory responses on both the LSNA and MAP to a sympathetic activated and pressor response. Pretreatment with the opioid antagonist, naloxone, significantly antagonized the sympathetic nervous and cardiovascular response to beta-END. It partially but significantly antagonized the MAP response to alphaMSH, but the sympathetic response was unaffected. Neither agouti protein nor naloxone altered the sympathetic nervous and cardiovascular response to ACTH. From these studies, we conclude that i.c.v. administration of alphaMSH and ACTH increases the LSNA and cardiovascular dynamics, whereas beta-END decreases it. And, the MC-4 receptor antagonist reverses the endorphin response and the opioid antagonist attenuates the alphaMSH response suggesting possible receptor or central neural pathway interactions between MC-4 and the opioid receptor mediated effects.