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Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors

Nature volume 394, pages 577–581 (1998)Cite this article

Abstract

The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion1,2. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels3. It has been shown using knockout mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function4. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

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Figure 1: Performance in Morris water-maze task in nociceptin receptor-deficient and wild-type mice.
Figure 2: Performance in multiple-trial passive avoidance test in nociceptin receptor-deficient and wild-type mice.
Figure 3: Expression of nociceptin precursor and nociceptin receptor in hippocampal regions.
Figure 4: Enhanced LTP in nociceptin receptor-deficient mice.

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Acknowledgements

We thank A. Sakamoto and I. Dobashi for help maintaining the mutant mice. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, the Japan Private School Promotion Foundation, the Uehara Memorial Foundation, the TMFC and the Life Science Foundation.

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Author notes

  1. Toshiya Manabe and Yukihiro Noda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurophysiology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, 113-8654, Tokyo, Japan

    Toshiya Manabe, Hiroyuki Katagiri & Tomoyuki Takahashi

  2. Department of Pharmacology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, 113-8654, Tokyo, Japan

    Miyuki Nishi & Hiroshi Takeshima

  3. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, School of Medicine, 466-8560, Nagoya, Japan

    Yukihiro Noda, Takayoshi Mamiya & Toshitaka Nabeshima

  4. Department of Anatomy, Kansai Medical University, Moriguchi, 570-8506, Osaka, Japan

    Takeshi Houtani & Tetsuo Sugimoto

  5. Department of Cell Biology, Cancer Institute, Kami-Ikebukuro, Toshima-ku, 170-8455, Tokyo, Japan

    Tetsuo Noda

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Correspondence to Hiroshi Takeshima.

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Manabe, T., Noda, Y., Mamiya, T. et al. Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors. Nature 394, 577–581 (1998). https://doi.org/10.1038/29073

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