Postsynaptic and presynaptic effects of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor, were investigated in an in vitro slice preparation of the rat thalamic reticular nucleus (NRT) and ventrobasal complex (VB). In NRT as well as VB, all tested neurons developed an outward current on application of 1 M N/OFQ. Basic properties of the N/OFQ-induced current included inward rectification, dependence on extracellular K ϩ , reduction by 100 M Ba ϩ , antagonistic effect of [Nphe 1 ]nociceptin(1-13)NH 2 , and sensitivity to internal GDP--S. Miniature IPSCs (mIPSCs) mediated by GABA A receptors in VB neurons were not affected by 1 M N/OFQ. In addition, paired-pulse depression of evoked IPSCs was unchanged, indicating a lack of presynaptic effects. By comparison, N/OFQ application resulted in a reduction in frequency of miniature EPSCs (mEPSCs) in a subpopulation of NRT neurons, whereas paired-pulse facilitation of evoked EPSCs was not altered. In either nucleus, current-clamp experiments revealed a hyperpolarization and associated decrease in input resistance in response to N/OFQ. Although N/OFQ had no measurable effect on calcium-mediated burst activity evoked by depolarizing steps from hyperpolarized values of the membrane potential, rebound bursts on relief of hyperpolarizing current steps were decreased. Slow thalamic oscillations induced in vitro by extracellular stimulation were dampened by N/OFQ in VB and NRT, as seen by delayed onset of rhythmic multiple-unit activity and reduction in amplitude and duration. We conclude that N/OFQ reduces the excitability of NRT and VB neurons predominantly through an increase of a G-proteincoupled inwardly rectifying K ϩ conductance.
Key words: thalamus; electrophysiology; patch-clamp; neuropeptide; potassium inward rectifier; synaptic transmissionA peptide termed nociceptin/orphanin FQ (N/OFQ) was recently identified as an endogenous heptadecapeptide agonist for the opioid receptor-like (ORL) receptor. Despite many structural homologies to opioid receptors, the ORL receptor shows lowaffinity binding to selective opioid agonists or antagonists. N/OFQ selectively activates the ORL receptor but not any opioid receptor subtype (Calo' et al., 2000b). In contrast to behavioral effects of classical opioids, N/OFQ was originally described as pronociceptive (Meunier et al., 1995;Reinscheid et al., 1995). In close succession, N/OFQ was shown to elicit a wide range of behavioral responses in view of pain processing, including hyperalgesia, reversal of opioid-mediated analgesia, analgesia, and allodynia, and was described as "opiate modulating" (for review, see Yamamoto et al., 1999;Barlocco et al., 2000;Brundege, 2000;Grisel and Mogil, 2000;Harrison and Grandy, 2000;Xu et al., 2000). On the cellular level, effects of N/OFQ resemble those elicited by opioids (Standifer and Pasternak, 1997), including inhibition of cAMP formation, modulation of Ca 2ϩ and K ϩ conductances, and regulation of transmitter release (Calo' et al., 2000b;Hawes et al., 200...