Autophagy in superficial spinal dorsal horn accelerates the cathepsin b-dependent morphine antinociceptive tolerance

Y. Hayashi, Y. Koga, X. Zhang, C. Peters, Y. Yanagawa, Z. Wu, T. Yokoyama, H. Nakanishi

研究成果: Contribution to journalArticle査読

12 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)384-394
ページ数11
ジャーナルNeuroscience
275
DOI
出版ステータス出版済み - 9 5 2014

All Science Journal Classification (ASJC) codes

  • 神経科学(全般)

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