We investigated the potential influence of opioid and melanotropic peptides on endogenous norepinephrine (NE) release from the A2 noradrenergic cell group of rats using a static, fixed-volume incubation procedure. Norepinephrine release from slices of caudal dorsomedial medulla (CDMM) was evoked by high potassium concentrations (20 and 60 mM) in a Ca2+-dependent and dose-related manner. Treatment with the potent melanotropin agonist [Nle4,D-Phe7]α-MSH(NDP-MSH) had no effet of K+-induced NE release. In conrast, human β-endorphin1-31 significantly reduced K+-stimulated NE release, but not in the presence of naloxone. The highly-selected μ-opioid agonist [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) also significantly reduced evoked NE release. The inhibitory effect of DAMGO was completely blocked by naloxone. Naloxone alone did not alter evoked NE release. The inhibitory effect of DAMGO was not enhanced by reducing the stimulatory concentration of K+. None of the peptides tested influenced basal NE release. These data indicate that melanotropin receptors do not regulate NE release in CDMM. In contrast, the opioid peptides DAMGO and β-endorphin inhibit K+-stimulated release of endogenous NE. These data suggest a role for μ-opioid receptors in controlling NE release from A2 noradrenergic neurons.