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

Yoshinori Hayashi, Y. Koga, X. Zhang, C. Peters, Y. Yanagawa, Hiro Take, Takeshi Yokoyama, Hiroshi Nakanishi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)384-394
Number of pages11
JournalNeuroscience
Volume275
DOIs
Publication statusPublished - Sep 5 2014

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Cathepsins
Autophagy
Morphine
Cathepsin B
Opioid Analgesics
Neurons
Microtubule-Associated Proteins
Cysteine Proteases
Gene Deletion
Acute Pain
Interneurons
Spinal Cord Dorsal Horn
Chronic Pain
Analgesics
Glutamic Acid
Spinal Cord
Up-Regulation
Therapeutics
Pharmacology
Light

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Autophagy in superficial spinal dorsal horn accelerates the cathepsin b-dependent morphine antinociceptive tolerance. / Hayashi, Yoshinori; Koga, Y.; Zhang, X.; Peters, C.; Yanagawa, Y.; Take, Hiro; Yokoyama, Takeshi; Nakanishi, Hiroshi.

In: Neuroscience, Vol. 275, 05.09.2014, p. 384-394.

Research output: Contribution to journalArticle

Hayashi, Yoshinori ; Koga, Y. ; Zhang, X. ; Peters, C. ; Yanagawa, Y. ; Take, Hiro ; Yokoyama, Takeshi ; Nakanishi, Hiroshi. / Autophagy in superficial spinal dorsal horn accelerates the cathepsin b-dependent morphine antinociceptive tolerance. In: Neuroscience. 2014 ; Vol. 275. pp. 384-394.
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