Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons

Neurons in the suprachiasmatic nucleus (SCN) constitute the principal circa dian pacemaker of mammals. in situ hybridization studies revealed expressio n of orphanin-FQ/nociceptin (OFQ/N) receptor (NOR) mRNA in the SCN, whereas no expression of mRNA for preproOFQ/N (ppOFQ/N) was detected. The presence of OFQ/N peptide in the SCN was demonstrated by radioimmunoassay. SCN neur ons (88%) responded dose-dependently to OFQ/N with an outward current (EC50 = 22.3 nM) that was reduced in amplitude by membrane hyperpolarization and reversed polarity near the theoretical potassium equilibrium potential. [P he(1)psi(Ch(2)-NH)Gly(2)]OFQ/N(1 -13)NH2 (3 mu M), a putative NOR antagonis t, activated a small outward current and significantly reduced the amplitud e of the OFQ/N-stimulated current. OFQ/N reduced the NMDA receptor-mediated increase in intracellular Ca2+. When injected unilaterally into the SCN of Syrian hamsters housed in constant darkness, OFQ/N (1-50 pmol) failed to a lter the timing of the hamsters' wheel-running activity However, injection of OFQ/N (0.160 pmol) before a brief exposure to light during the mid-subje ctive night significantly attenuated the light-induced phase advances of th e activity rhythm. These data are consistent with the interpretation that O FQ/N acting ai:specific receptors modulates the activity of SCN neurons and , thereby, the response of the circadian clock to light.