Distinct effects of nociceptin analogs on scopolamine-induced memory impairment in mice.

Nociceptin, also known as orphanin FQ, binds to opioid receptor like-1 (NOP) receptors. Nociceptin and NOP receptor play important roles in several physiological functions in the central nervous system. We reported that although high doses of nociceptin impaired learning and memory and these effects were blocked by nocistatin, naloxone benzoylhydrazone and [NPhe(1)]nociceptin(1-13)NH(2), low doses of nociceptin improved scopolamine- or mecamylamine-induced impairment of learning and memory, and these ameliorating effects were not blocked by these antagonists. In the present study, to confirm our previous findings, the effects of [Arg(14), Lys(15)]nociceptin and [(pF)Phe(4)]nociceptin(1-13)NH(2), highly potent and long-lasting nociceptin analogs, on the memory impairment induced by scopolamine using the Y-maze and step-down type passive avoidance tests were investigated. [Arg(14), Lys(15)]Nociceptin (0.1 and/or 1 pmol/mouse, i.c.v.) significantly improved impairment of memory function. Although this analog was about 30 times more potent than nociceptin, the doses ameliorating these memory impairments were comparable to those of the natural ligand nociceptin. The ameliorating effects of [Arg(14), Lys(15)]nociceptin were not blocked by an NOP receptor antagonist, [NPhe(1)]nociceptin(1-13)NH(2). Interestingly, another potent nociceptin analog, [(pF)Phe(4)]nociceptin(1-13)NH(2) could not improve impairment of memory function. These results confirmed that there are novel mechanisms underlying these ameliorating effects and these seem not to be mediated via an NOP receptor.