title: Autophagy in superficial spinal dorsal horn accelerates the cathepsin B-dependent morphine antinociceptive tolerance.
abstract: Opioids are the most widely used analgesics in the treatment of severe acute and chronic pain. However, opioids have many adverse side effects, including the development of antinociceptive tolerance after long-term use. The antinociceptive tolerance of opioids has limited their clinical use. A recent study has reported that autophagy is responsible for morphine-induced neuronal injury. However, little is known about the role of autophagy in morphine antinociceptive tolerance. In the present study, chronic morphine administration was found to induce the expression of autophagy-related proteins, including Beclin1 and microtubule-associated protein light chain 3 (LC3)-II, in GABAergic interneurons in the superficial layer (lamina I-II) of the spinal cord. A single intrathecal administration of autophagy inhibitors, 3-methyladenine (3MA) or wortmannin, inhibited the development of antinociceptive tolerance in a dose-dependent manner. Autophagy in the lamina I-II neurons was associated with increased level of cathepsin B (CatB), a lysosomal cysteine protease. The pharmacological blockade or gene deletion of CatB markedly prevented the development of morphine antinociceptive tolerance. Furthermore, the intrathecal administration of 3MA suppressed the upregulation of CatB 5 days after morphine administration. Finally, CatB deficiency inhibited the increased release probability of glutamate in the lamina I neurons after chronic morphine treatment. These observations suggest that the dysfunction of the spinal GABAergic system induced by CatB-dependent excessive autophagy is partly responsible for morphine antinociceptive tolerance following chronic treatment.
authors: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: yoshinor@dent.kyushu-u.ac.jp.
authors: Y
authors: Y
authors: Hayashi
authors: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Dental Anesthesiology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Y
authors: Y
authors: Koga
authors: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: X
authors: X
authors: Zhang
authors: Institut für Molekulare Medizin und Zellforschung Zentrum für Biochemie und Molekulare Zellforschung Albert-Ludwigs-Universität Freiburg, Stefan-Meier-Strasse 17, 79104 Freiburg, Germany.
authors: C
authors: C
authors: Peters
authors: Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors: Y
authors: Y
authors: Yanagawa
authors: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Z
authors: Z
authors: Wu
authors: Department of Dental Anesthesiology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: T
authors: T
authors: Yokoyama
authors: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, 5, Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan. Electronic address: nakan@dent.kyshu-u.ac.jp.
authors: H
authors: H
authors: Nakanishi
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002401:Cathepsin B / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials; D015151:Immunoblotting; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D002401:Cathepsin B; C533915:Ctsb protein, mouse
keywords: GABAergic interneuron; autophagy; cathepsin B; disinhibition; microglia; morphine antinociceptive tolerance