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Glycogen Synthase Kinase-3 Inhibitors Block Morphine-Induced Locomotor Activation, Straub Tail, and Depression of Rearing in Mice Via a Possible Central Action

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Abstract

We investigated morphine-induced Straub’s tail reaction (STR) in mice pretreated with or without glycogen synthase kinase-3 (GSK-3) inhibitors (SB216763 and AR-A014418) by using a newly modified, infrared beam sensor-based automated apparatus. Mice treated with a single injection of morphine (30 mg/kg, i.p.) showed a significant STR with a plateau level at a time point of 20 min after morphine challenge. Pretreatment of mice with SB216763 (5 mg/kg, s.c.) or AR-A014418 (3 mg/kg, i.p.) significantly inhibited morphine-induced STR and attenuated the duration of STR in a dose-dependent fashion. In the striatum and the nucleus accumbens, expression of pGSK-3βTyr216 but not GSK3β or pGSK-3βSer9 was largely but not significantly reduced after treatment with SB216763 (5 mg/kg, s.c.) in combination with/without morphine, indicating that the inhibitory effect of GSK-3 inhibitors on morphine-induced STR and hyperlocomotion might not depend on the direct blockade of GSK-3β function. In constipated mice after morphine challenge (30 mg/kg), the effect of GSK-3 inhibitors on gastrointestinal transit was examined to reveal whether the action of GSK-3 inhibitors on morphine effects was central and/or peripheral. Pretreatment with SB216763 (5 mg/kg) did not block constipation in morphine-injected mice. The mechanism of action seems to be central but not peripheral, although the underlying subcellular mechanism of GSK-3 inhibitors is not clear. Our measurement system is a useful tool for investigating the excitatory effects of morphine in experimental animals.

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Data Availability

The datasets generated during and/or analyzed during the current study that support the findings of this study are available from the corresponding author, Junichi Kitanaka, upon reasonable request.

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Funding

This study was supported, in part, by grants from Japan Society for the Promotion of Science KAKENHI (Grant Nos. 21K06591 to JK; 22K10151 to KT).

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Author notes

  1. Junichi Kitanaka, Nobue Kitanaka and Kazuo Tomita have contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Drug Addiction and Experimental Therapeutics, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8530, Japan

    Junichi Kitanaka

  2. Department of Pharmacology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, 663-8501, Japan

    Nobue Kitanaka

  3. Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544, Japan

    Kazuo Tomita, Kento Igarashi & Tomoaki Sato

  4. Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA

    F. Scott Hall

  5. VA Maryland Healthcare System, Baltimore, MD, 21201, USA

    George R. Uhl

  6. Departments of Neurology and Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    George R. Uhl

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  1. Junichi Kitanaka
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  2. Nobue Kitanaka
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Junichi Kitanaka, Nobue Kitanaka, Kazuo Tomita, and F. Scott Hall. The first draft of the manuscript was written by Junichi Kitanaka, Nobue Kitanaka, Kazuo Tomita, and F. Scott Hall, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junichi Kitanaka.

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Animal handling and care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (8th edition, Institute of Laboratory Animal Resources-National Research Council, National Academy Press, 2011), and all experiments were reviewed and approved by the Institutional Animal Research Committee of Hyogo Medical University.

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Kitanaka, J., Kitanaka, N., Tomita, K. et al. Glycogen Synthase Kinase-3 Inhibitors Block Morphine-Induced Locomotor Activation, Straub Tail, and Depression of Rearing in Mice Via a Possible Central Action. Neurochem Res 48, 2230–2240 (2023). https://doi.org/10.1007/s11064-023-03902-2

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