Neuronal mechanism of nociceptin-induced modulation of learning and memory: Involvement of N-methyl-D-aspartate receptors

Abstract

Nociceptin (also called orphanin FQ) is an endogenous heptadecapeptide that activates the opioid receptor-like 1 (ORL 1 ) receptor. Nociceptin system not only affects the nociception and locomotor activity, but also regulates learning and memory in rodents. We have previously reported that long-term potentiation and memory of ORL 1 receptor knockout mice are enhanced compared with those in wild-type mice. Here, we show the neuronal mechanism of nociceptin-induced modulation of learning and memory. Retention of fear-conditioned contextual memory was significantly enhanced in the ORL 1 receptor knockout mice without any changes in cued conditioned freezing. Inversely, in the wild-type mice retention of contextual, but not cued, conditioning freezing behavior was suppressed by exogenous nociceptin when it was administered into the cerebroventricle immediately after the training. ORL 1 receptor knockout mice exhibited a hyperfunction of N-methyl-D-aspartate (NMDA) receptor, as evidenced by an increase in [ 3 H]MK-801 binding, NMDA-evoked 45 Ca 2 þ uptake and activation of Ca 2 þ /calmodulin-dependent protein kinase II (CaMKII) activity and its phosphorylation as compared with those in wild-type mice. The NMDA-induced CaMKII activation in the hippocampal slices of wild-type mice was significantly inhibited by exogenous nociceptin via a pertussis toxin-sensitive pathway. However, the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor GluR1 subunit at Ser 831 and Ser 845, and NMDA receptor subunit NR2B at Thr 286 were phosphorylated similarly after NMDA receptor stimulation in both type of mice. The expressions of GluR1 and GluR2 also did not change, but the levels of polysialylated form of neuronal cell adhesion molecule (N-CAM) were reduced in the ORL 1 receptor knockout as compared with wild-type mice. These results suggest that nociceptin system negatively modulates learning and memory through the regulation of NMDA receptor function and the expression of N-CAM. Molecular Psychiatry (2003Psychiatry ( ) 8, 752-765. doi:10.1038 Keywords: nociceptin/orphanin FQ; ORL 1 receptor; Knockout mice; hippocampus; NMDA Opioid receptors are negatively coupled to adenylate cyclase through Gi/o proteins and mediate the inhibition of forskolin-induced cAMP accumulation by morphine and endogenous opioid peptides. Opioid receptor agonists have receptor subtypespecific actions on not only the nociceptive thresholds but also synaptic transmission and long-term potentiation (LTP) in the hippocampus. Thus, opioid system modulates certain forms of learning and memory.

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

“…These findings strongly suggest that the NOP receptor agonist selectively interferes with mnemonic processes related to long-term consolidation processes. This is in line with previous studies showing that N/OFQ abolishes long-term retention of fear conditioning and passive avoidance when administered post-training (Mamiya et al, 2003;Roozendaal et al, 2007). Interestingly, when injected into the dorsal hippocampus, N/OFQ severely impaired long-term recognition memory formation, without any apparent effects on sensorimotor functions.…”

“…N/OFQ and its receptor are densely expressed in brain regions associated with learning and memory processes, such as the hippocampus, the amygdala, and the cerebral cortex (Darland and Grandy, 1998;Neal et al, 1999a,b). 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).…”

“…Furthermore, combined treatments with subthreshold doses produced a synergistic inhibition of memory performances and ERK activation. These results are complementary to those reported in NOP receptor knock-out mice showing that antagonism of N/OFQ transmission improves fear memory through NMDA receptor-dependent mechanisms (Mamiya et al, 2003). They also provide the first evidence that NOP and NMDA receptors converge on common ERK pathway in the hippocampus to regulate memory formation.…”

“…Previous studies have demonstrated the role of N/OFQ-NOP receptor system in working memory, spatial and fear learning (Hiramatsu and Inoue, 1999;Redrobe et al, 2000;Higgins et al, 2002;Mamiya et al, 2003;Sandin et al, 2004;Roozendaal et al, 2007), but the contribution of this novel neuropeptide system in modulation of recognition memory have not been investigated. Here, we show that intracerebroventricular infusion of N/OFQ or systemic administration of the selective NOP receptor agonist, Ro64-6198, impairs long-term object recognition memory formation in mice.…”

“…By blocking Ca 2ϩ current and inhibiting cAMP production (New and Wong, 2002), NOP receptor can suppress the activation of multiple cascades that ultimately converge on ERK, and thereby disrupts NMDA receptor-mediated recognition memory formation. In this regard, Mamiya et al (2003) have shown that NOP and NMDA receptors modulate in an opposing manner the activity of Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) in hippocampal slice. CaMKII was proposed to act as a trigger of Ras/Raf/MEK cascade (Micheau and Riedel, 1999;Blitzer et al, 2005), and may thus be one potential upstream target that could relay the influences of NOP and NMDA receptors on ERK activity at postsynaptic level.…”