Journal
NEUROSCIENCE
Volume 275, Issue -, Pages 384-394Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2014.06.037
Keywords
morphine antinociceptive tolerance; autophagy; cathepsin B; GABAergic interneuron; disinhibition; microglia
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Funding
- Japan Science and Technology Agency, Core Research for Evolutional Science and Technology
- Ministry of Education, Science, and Culture Japan, and Takeda Science Foundation, Japan [24791979]
- Grants-in-Aid for Scientific Research [24390416, 24791979] Funding Source: KAKEN
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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. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
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