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

Nociceptin (also called orphanin FQ) is an endogenous heptadecapeptide that activates the opioid receptor-like 1 (ORL₁) 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 ORL₁ 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. ORL₁ receptor knockout mice exhibited a hyperfunction of N-methyl-D-aspartate (NMDA) receptor, as evidenced by an increase in [ ³H]MK-801 binding, NMDA-evoked ⁴⁵Ca²⁺ uptake and activation of Ca²⁺/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 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor GluR1 subunit at Ser⁸³¹ and Ser⁸⁴⁵, and NMDA receptor subunit NR2B at Thr²⁸⁶ 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 ORL₁ 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.