Functional selectivity of orphanin FQ for its receptor coexpressed with potassium channel subunits in Xenopus laevis oocytes.

An opioid-like receptor has been cloned by several groups of researchers and recently shown to be activated by an endogenous heptadecapeptide termed orphanin FQ (or nociceptin). We isolated the corresponding mouse cDNA and coexpressed it in Xenopus laevis oocytes with the potassium channel subunits Kir3.1 (GIRK1) and Kir3.4 (CIR, rcKATP). Orphanin FQ evoked potassium currents, with 50% of the maximal effect at approximately 1 nM; [Tyr1]orphanin FQ was equally effective, and des-pheorphanin FQ was without activity. Dynorphin A, dynorphin(1-9), dynorphin(1-13), and alpha-neoendorphin were > 100 times less potent, and other agonists active at mu-, delta-, and kappa-opioid receptors had no effect. Naloxone (1 microM) and norbinaltorphimine (1 microM) had no antagonist action. Conversely, oocytes expressing kappa receptors responded to dynorphin (half-maximal concentration, 0.3 nM) but not to orphanin FQ. Thus, both kappa and orphanin FQ receptors readily couple to potassium channels, but the highly selective activation by dynorphin and orphanin FQ is consistent with distinct functional pathways in vivo.