To assess the role of endogenous opiates on the hormonal and cardiovascular responses to moderate hemorrhage (H) and/or nociceptor activation, naloxone (Nx; 100 μg/kg, iv) was given coincident with H (10 ml/kg), tooth pulp nerve stimulation (TP), or H plus TP in anesthetized cats. We have previously reported that TP potentiated the ACTH response to H. Nx treatment did not affect this TP potentiation of ACTH after H, nor did Nx affect the ACTH response to H alone. This suggested that the interaction between nociceptor and baroreceptor afferent nerves, which may underlie the observed TP potentiation of ACTH release after H in the anesthetized cat, was not dependent upon naloxone-sensitive opiate pathways. In contrast, Nx attenuated the fall in arterial pressure during H or H plus TP and completely blocked the normally observed hyperglycemia. Catecholamines showed a prompt rise during H or H plus TP in Nx-treated animals. Thus, altered adrenomedullary hormone release cannot account for the attenuated fall in blood pressure or the inhibition of hyperglycemia during H or H plus TP. Nx presented alone or in combination with TP did not significantly affect any measured variable. To determine if Nx acted directly at the level of the liver to block H-induced hyperglycemia, a second group of animals received intraportal injections of Nx (20, 50, or 100 μg/kg) before H. Nx did not block the rise in glucose after H, although each of the three doses of Nx significantly attenuated the early (at +1 min) fall in blood pressure. Portal venous samples of glucagon and insulin during H were not significantly affected by Nx. These results suggest that 1) naloxone-sensitive endogenous opiate receptors are not necessary for the rise in ACTH during H or for the TP potentiation of H-induced increases in ACTH; 2) the fall in mean arterial pressure and the rise in glucose during H are selectively attenuated by Nx independent of significant changes in peripheral catecholamine levels when compared to Nx untreated animals; and 3) finally, Nx does not act directly at the liver to block the H-induced rise in glucose, but, rather, is effectively cleared from the circulation by the liver.