DYNORPHIN PEPTIDES - ANTAGONISTS OF MELANOCORTIN RECEPTORS

Purpose. To identify possible targets that mediate the non-opioid effe cts of dynorphin A (DynA), effects that include inflammation and aggra vation of traumatic nerve injury. Method We examined dynorphin peptide s for functional interaction with the closely related melanocortin (MC ) system. Results. DynA-(1-13)NH2 and other related opioid dynorphin p eptides antagonize the human MC1, MC3 and MC4 receptors, and an amphib ian MC receptor, with dissociation constants (K-d'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 dyn orphin, which require micromolar concentrations. Dynorphin also antago nizes the adrenocorticotropic hormone (ACTH; MC2) receptor and an MC-l ike receptor endogenous to COS-7 cells, but with lower efficacy. In co ntrast DynA had no effect on seven control receptors and was only weak ly effective at two others. Metabolites of dynorphin derived from clea vage of the amino terminal Tyr residue, such as DynA(2-17), lack opioi d activity yet still produce a number of well established non-opioid e ffects. These des-Sr derivatives also antagonized each of the five MC receptors examined. Conclusions. DynA peptides were found to antagoniz e MC receptors in vitro with potencies that parallel those reported fo r pharmacological non-opioid effects of dynorphins in vivo. The combin ation of DynA and its active metabolites may reach levels sufficient t o inhibit MC receptors physiologically. Dynorphin inhibition of MC rec eptors could prove to be an example of crosstalk between two distinct yet phylogenetically related neurotransmitter systems.