Modulation of vestibular function by nociceptin/orphanin FQ: an in vivo and in vitro study

The effects of nociceptin (orphanin FQ) on medial vestibular nucleus (MVN) neurons in vitro, and on vestibulo-ocular reflex (VOR) function in vivo, were investigated in order to determine the role of 'opioid-like orphan' (ORL1) receptors in modulating vestibular reflex function in the rat. Nociceptin (100 nM-1 microM) potently inhibited the spontaneous discharge of the majority (86%) of MVN neurons tested in the rat dorsal brainstem slice preparation in vitro. This inhibition was dose-dependent and persisted after blockade of synaptic transmission in low Ca2+/Co2+ medium. The inhibitory effects were insensitive to the opioid antagonist naloxone, but were effectively antagonised by the selective ORL1 receptor antagonist, [Phe1Psi(CH2-NH)Gly2]Nociceptin(1-13)NH2. The majority of MVN neurons ( approximately 70%) were inhibited by both nociceptin and the delta-opioid receptor agonist, [D-ala2, D-leu5]-enkephalin (DADLE), while a minority of cells (approximately 30%) were selectively responsive either to DADLE or to nociceptin, but not both. Co-application of nociceptin and DADLE to neurons that were responsive to both agonists, resulted in an inhibitory response that was the same as or less than the inhibition evoked by either agonist alone. Intracellular whole-cell patch clamp recordings from identified Type A and Type B MVN cells showed that both these cell types are responsive to nociceptin, which induced membrane hyperpolarisation and decrease in input resistance consistent with its known effects on membrane K currents in other cell types. In alert rats, i.c.v. injection of nociceptin caused a significant decrease in the gain of the hVOR and resulted in a prolongation of post-rotatory nystagmus in darkness. The decrease in VOR gain and the increase in the VOR time-constant was significant even at low doses of nociceptin which did not cause other observable behavioural effects. These findings demonstrate that endogenously released nociceptin may have a hitherto unexplored role in the functional modulation of the neural pathways that mediate vestibular reflexes in vivo.