Nociceptin receptor impairs recognition memory via interaction with NMDA receptor-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in the hippocampus

Strong evidence suggests a role for nociceptin/orphanin FQ ( N/OFQ) neuropeptide and its receptor ( NOP) in cognition. However, the signaling mechanisms underlying N/OFQ modulation of memory are less understood. Here, we show that intracerebroventricular or intrahippocampal infusions of N/OFQ impair long-term memory formation in the mouse object recognition task. The synthetic NOP receptor agonist, ( 1S, 3aS)-8-( 2,3,3a, 4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[ 4.5] decan-4-one ( Ro64-6198), administered systemically, also produced amnesic effects that were blocked by coinfusion of the NOP receptor antagonist, [ Nphe1, Arg14, Lys15] nociceptin-NH2 ( UFP-101), into the dorsal hippocampus. In contrast, Ro64-6198 had no effect on short-term memory or recall performances. Immunoblotting analysis revealed a strong suppressive action of Ro64-6198 on learning-induced upregulation of hippocampal extracellular signal-regulated kinase ( ERK) phosphorylation, which is crucial for long-term information storage. Accordingly, pharmacological inhibition of ERK activation after systemic injection of SL327 [alpha-[ amino[( 4-aminophenyl)thio] methylene]-2-( trifluoromethyl) benzene acetonitrile], a selective inhibitor of the upstream kinase MEK ( mitogen-activated protein kinase kinase), abolished long-term recognition memory formation. The noncompetitive NMDA receptor antagonist ( +)-5-methyl-10,11-dihydro-5H-dibenzo [ a, d] cyclohepten-5,10-imine maleate ( MK-801), given systemically, also suppressed ERK activation and disrupted recognition memory. In contrast, no effect of MK-801 was observed on recall, as for Ro64-6198. When administered concurrently at subthreshold doses, Ro64-6198 and MK-801 synergistically suppressed hippocampal ERK activation and impaired long-term memory formation. Under resting conditions, neither Ro64-6198 nor MK-801 affected spontaneous ERK activity in the hippocampus at the amnesic doses whereas at higher doses, only MK-801 had a suppressive effect. We conclude that N/OFQ-NOP receptor system negatively regulates long-term recognition memory formation through hippocampal ERK signaling mechanisms. This modulation may in part take place by inhibiting glutamatergic function at the NMDA receptor.