Nociceptin and its metabolite attenuate U0126-induced memory impairment through a nociceptin opioid peptide (NOP) receptor-independent mechanism |
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| Authors: | Masaya Miwa Shogo Uchida Fumika Horiba Hiroshi Takeshima Toshitaka Nabeshima Masayuki Hiramatsu |
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| Affiliation: | 1. Laboratory of Neuropsychopharmacology, Graduate School of Environmental and Human Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan;2. Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan;3. Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan;1. Department of Dermatology, Shandong Ji-ning No. 1 People’s Hospital, Shandong Province 272011, PR China;2. Department of Dermatology, The Second Hospital Affiliated of Soochow University, SuZhou, Jiangsu Province 215000, PR China;3. Department of Oncology, Shandong Ji-ning No. 1 People’s Hospital, Shandong Province 272011, PR China;1. Department of Veterinary Medicine and Applied Radiological Science Research Institute, Jeju National University, Ara-dong 1, Jeju 690-756, South Korea;2. Laboratories of Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan;3. Department of Chemistry, College of Natural Sciences, Jeju National University, Ara-dong 1, Jeju 690-756, South Korea;4. Department of Nuclear and Energy Engineering, Jeju National University, Ara-dong 1, Jeju 690-756, South Korea;1. Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China;2. State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;3. The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China;1. Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065 Hubei Province, China;2. Department of Pharmacy, Yangtze River Shipping General Hospital, Wuhan, 430010 Hubei Province, China;3. Drug research base of cardiovascular and cerebral vascular, Wuhan University of Science and Technology, China;1. Department of Physics, Tohoku University, Sendai 980-8578, Japan;2. Kavli IPMU, TODIAS, University of Tokyo, Kashiwa 277-8583, Japan;1. Herbal Research Section, CSIR–Indian Institute of Toxicology Research, Post Box No. 80, Mahatma Gandhi Marg, Lucknow 226001, India;2. Academy of Scientific and Innovative Research, India;3. Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India |
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| Abstract: | Nociceptin binds to nociceptin opioid peptide (NOP) receptors. We reported that although high doses of nociceptin impaired memory function and that these effects were mediated via NOP receptors, low doses of nociceptin attenuated the memory impairment, and these attenuating effects were not mediated via NOP receptors. Even very low doses of nociceptin were biologically active and suggested a certain binding site for this peptide, but the mechanism underlying this attenuating effect has not yet been elucidated. In the present study, we investigated the effect of an intrahippocampal injection (i.h.) of nociceptin on memory impairment induced by U0126, a MEK inhibitor, and Rp-cAMPS, a PKA inhibitor in a step-down type passive avoidance test. U0126 (2.63 nmol/mouse, i.h.) impaired memory formation and training-dependent phosphorylation of ERK2 in the hippocampus. Co-administration of nociceptin (10 fmol/mouse) significantly attenuated memory impairment, while it did not attenuate the inhibition of training-dependent phosphorylation of ERK2 induced by U0126. On the other hand, nociceptin did not attenuate memory impairment induced by Rp-cAMPS (0.448 nmol/mouse, i.h.). Nociceptin (1 fmol/mouse) also attenuated U0126 (5.26 nmol/mouse)-induced memory impairment in NOP receptor knockout mice. Nociceptin was reported to metabolize into fragments (1–13) and (14–17) in vivo, which showed pharmacological activities without affecting NOP receptors. Our findings showed that nociceptin (14–17) (1 fmol/mouse) also attenuated U0126-induced memory impairment, while nociceptin (1–13) (0.1–10 fmol/mouse) did not attenuate memory impairment. These results suggest a novel action site or mechanism for the attenuating effects of nociceptin and its metabolite, and the sequence of nociceptin (14–17) is a critical structure. |
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