To identify possible targets that mediate the non-opioid effects of dynorphin-A (DynA), effects that include inflammation and aggravation of traumatic nerve injury.We examined dynorphin peptides for functional interaction with the closely related melanocortin (MC) system.DynA-(1-13)NH2 and other related opioid dynorphin peptides antagonize the human MC1, MC3 and MC4 receptors, and an amphibian MC receptor, with dissociation constants (Kd's) of 40 to 150 nM. The affinity of dynorphin's interaction with MC receptors is therefore greater than with other previously proposed non-opioid targets of dynorphin, which require micromolar concentrations. Dynorphin also antagonizes the adrenocorticotropic hormone (ACTH; MC2) receptor and an MC-like receptor endogenous to COS-7 cells, but with lower efficacy. In contrast DynA had no effect on seven control receptors and was only weakly effective at two others. Metabolites of dynorphin derived from cleavage of the amino terminal Tyr residue, such as DynA(2-17), lack opioid activity yet still produce a number of well established non-opioid effects. These des-Tyr derivatives also antagonized each of the five MC receptors examined.DynA peptides were found to antagonize MC receptors in vitro with potencies that parallel those reported for pharmacological non-opioid effects of dynorphins in vivo. The combination of DynA and its active metabolites may reach levels sufficient to inhibit MC receptors physiologically. Dynorphin inhibition of MC receptors could prove to be an example of crosstalk between two distinct yet phylogenetically related neurotransmitter systems.