Orphanin FQ/Nociceptin Inhibits Synaptic Transmission and Long-Term Potentiation in Rat Dentate Gyrus Through Postsynaptic Mechanisms

Abstract

Orphanin FQ/nociceptin (OFQ), a recently characterized natural ligand for the opioid receptor-like 1 (ORL1) receptor, shares structural similarity to the endogenous opioids. Our previous study found that OFQ, like classical opioids, modulated synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region, suggesting a modulatory role for OFQ in synaptic plasticity involved in learning and memory. In the present study we investigated the action of OFQ in the dentate gyrus and explored possible underlying cellular mechanisms. Field potential recordings showed that OFQ significantly inhibited excitatory synaptic transmission and LTP induction in the dentate lateral perforant path. In the presence of OFQ, the excitatory postsynaptic potential (EPSP) slope-population spike (E-S) curve was shifted to the right, and no significant change was found in paired-pulse facilitation, suggesting a postsynaptic mechanism responsible for the inhibition of synaptic transmission. Under whole cell voltage-clamp conditions, bath application of OFQ activated K+ currents in most granule cells tested at a holding potential of -50 mV, suggesting that OFQ could reduce the excitability of dentate granule cells by hyperpolarizing cell membranes. OFQ also inhibited the amplitude of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) without affecting alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs. This inhibition was not blocked by opioid receptor antagonists. Furthermore, the inward currents evoked by focal application of NMDA to granule cells were suppressed by OFQ in a dose-dependent manner, suggesting that OFQ may suppress LTP by inhibiting the function of postsynaptic NMDA receptors. These results demonstrate that OFQ may negatively modulate synaptic transmission and plasticity in the dentate gyrus through postsynaptic mechanisms, including hyperpolarization of granule cells as well as inhibition of the function of postsynaptic NMDA receptors/channels in dentate granule cells.

Nociceptin Receptor Impairs Recognition Memory via Interaction with NMDA Receptor-Dependent Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in the Hippocampus

“…NOP receptors are also located on interneurons and pyramidal cells throughout the hippocampus (Houtani et al, 2000), and can therefore directly modulate NMDA receptor function at the postsynaptic level. Consistent with this view, electrophysiological studies showed that exogenous as well as endogenous N/OFQ potently inhibits NMDA receptor-dependent long-term potentiation through direct action on pyramidal and granule cells in the hippocampus (Yu and Xie, 1998;Bongsebandhu-phubhakdi and Manabe, 2007). NOP receptor is a G-protein-coupled receptor that negatively regulates the activity of adenylate cyclases, inhibits voltage-gated Ca 2ϩ channels and activates inward rectifying K ϩ channels.…”

“…Furthermore, NOP receptor activation with N/OFQ or synthetic agonists impairs memory performances in a variety of cognitive tasks in rodents (Sandin et al, 1997;Hiramatsu and Inoue, 1999;Redrobe et al, 2000;Higgins et al, 2002;Mamiya et al, 2003;Liu et al, 2007;Roozendaal et al, 2007), whereas the deletion of NOP receptor or preproN/OFQ gene produces the opposite effects (Manabe et al, 1998;Higgins et al, 2002;Mamiya et al, 2003). Consistent with these findings, electrophysiological studies showed that N/OFQ potently inhibits synaptic transmission and synaptic plasticity in the hippocampus and the amygdala (Yu et al, 1997;Meis and Pape, 1998;Yu and Xie, 1998;Wei and Xie, 1999; Bongsebandhu-phubhakdi and Manabe, 2007).…”

“…Electrophysiological studies indicate that N/OFQ inhibits synaptic transmission and plasticity in the hippocampus through suppression of glutamatergic function at the NMDA receptor (Manabe et al, 1998;Yu and Xie, 1998;Wei and Xie, 1999;Bongsebandhu-phubhakdi and Manabe, 2007). Based on these findings, we hypothesized that NOP receptors may regulate recognition memory by interacting with NMDA receptor signaling in the hippocampus.…”

[Nphe1]‐Nociceptin (1‐13)‐NH2, a nociceptin receptor antagonist, reverses nociceptin‐induced spatial memory impairments in the Morris water maze task in rats

“…In addition, electrophysiological studies have demonstrated that OP 4 /nociceptin receptors can couple to inwardly rectifying K + channels in hippocampal preparations, and that nociceptin induces the activation of such channels (Ikeda et al, 1997). Furthermore, nociceptin inhibited synaptic transmission and synaptic plasticity such as long-term potentiation (LTP) in the rat hippocampus and dentate gyrus (Yu et al, 1997;Yu & Xie, 1998). [Nphe 1 ]-Nociceptin (1-13)-NH 2 , by blocking nociceptin receptors, may prevent such agonist-induced e ects and hence antagonize nociceptin-induced impairments of learning and memory.…”

Synaptic Effects Induced by Alcohol

“…At the cellular level, nociceptin acts at NOR to augment K + conductances in amygdalar (Meis andPape 1998, 2001), hippocampal (Amano et al 2000;Ikeda et al 1997;Madamba et al 1999;Tallent et al 2001;Yu and Xie 1998) and thalamic neurons (Meis 2003;Meis et al 2002), thus depressing cell excitability. Nociceptin has also been shown to decrease Ca 2+ currents (Abdulla and Smith 1997;Calo et al 2000;Connor et al 1999;Henderson and McKnight 1997;Larsson et al 2000) and reduce the amplitude of both non-NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) and IPSCs in rat lateral amygdala (Meis et al 2002).…”