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

Molecular Psychiatry volume 8, pages 752–765 (2003)Cite this article

Abstract

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 ORL1 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.

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Acknowledgements

We are very thankful to Drs Takeshima and Nishi at Tohoku University for supplying the ORL1 receptor knockout mice. This work was supported, in part, by a Grant-in-Aid for Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Research Program from the Ministry of Education, Culture, Sports Science and Technology of Japan, the Health Sciences Research Grants for Research on Pharmaceutical and Medical Safety from the Ministry of Health, Labor and Welfare of Japan, and the Hibino Memorial Fund and the Kyousaidan Foundation Fund.

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Authors and Affiliations

  1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Mamiya, K Yamada, Y Miyamoto, Y Noda & T Nabeshima

  2. Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan

    T Mamiya

  3. Department of Clinical Pharmacy, Laboratory of Experimental Therapeutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan

    K Yamada

  4. Department of Molecular Genetics, National Institute for Longevity Sciences, Oobu, Japan

    Y Miyamoto

  5. EPHE Quantitative Cell Biology, Montpellier University, Montpellier Cedex, France

    N König

  6. Department of Physiology, Kagawa Medical University, Kagawa, Japan

    Y Watanabe

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  1. T Mamiya
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Correspondence to T Nabeshima.

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Mamiya, T., Yamada, K., Miyamoto, Y. et al. Neuronal mechanism of nociceptin-induced modulation of learning and memory: Involvement of N-methyl-D-aspartate receptors. Mol Psychiatry 8, 752–765 (2003). https://doi.org/10.1038/sj.mp.4001313

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