THE PEPTIDE ORPHANIN FQ INHIBITS BETA-ENDORPHIN NEURONS AND NEUROSECRETORY-CELLS IN THE HYPOTHALAMIC ARCUATE NUCLEUS BY ACTIVATING AN INWARDLY-RECTIFYING K+ CONDUCTANCE

Orphanin FQ (OFQ) is a novel heptadecapeptide whose structure resemble s that of dynorphin A(1-17) Its receptor shares appreciable homology w ith mu-, delta- and kappa-opioid receptors, and is highly expressed in the hypothalamus. The present study examined the effects of OFQ on ne urons within the arcuate nucleus (ARC) of the mediobasal hypothalamus, using intracellular recordings from coronal slices. In current clamp, OFQ produced a hyperpolarization of ARC neurons, including those immu nopositive for beta-endorphin, tyrosine hydroxylase and gonadotropin-r eleasing hormone. This hyperpolarization was dose-dependent, insensiti ve to antagonism by naloxone and was associated with a decrease in inp ut resistance. In voltage clamp, OFQ produced an outward current assoc iated with an increase in conductance. Varying the extracellular K+ co ncentration shifted the reversal potential for the OFQ response to the degree predicted by the Nernst equation. Furthermore, barium chloride markedly attenuated both the OFQ-induced hyperpolarization and decrea se in input resistance. Administration of maximally effective concentr ations of OFQ, followed by coadministration of maximal concentrations of either OFQ and the CL-opioid receptor agonist DAMGO or OFQ and the GABA(B) receptor agonist baclofen produced additive hyperpolarizations and outward currents. If DAMGO was applied first, followed by the coa dministration of DAMGO and OFQ, then the responses were occluded. Take n together, these results indicate that OFQ inhibits beta-endorphin ne urons, as well as A(12) dopamine and GnRH neurosecretory cells, within the ARC by activating a subset of inwardly-rectifying K+ channels. Th is suggests that OFQ is not only an antiopioid peptide, but that it al so modulates the hypothalamo-pituitary axis and, ultimately, reproduct ive behavior.