Abstract | BACKGROUND: METHODS: Rat and mouse formalin, hot-plate, and tail-flick tests were used, and spinal DAAO expression and hydrogen peroxide level were measured. Sample size of animals was six in each study group. RESULTS: Subcutaneous and intrathecal DAAO inhibitors, including 5-chloro-benzo[d] isoxazol-3-ol, AS057278, and sodium benzoate, completely prevented and reversed morphine antinociceptive tolerance in the formalin, hot-plate, and tail-immersion tests, with a positive correlation to their DAAO inhibitory activities. Intrathecal gene silencers, small interfering RNA/DAAO and small hairpin RNA/DAAO, almost completely prevented morphine tolerance. Intrathecal 5-chloro-benzo[d] isoxazol-3-ol and small interfering RNA/DAAO completely prevented increased spinal hydrogen peroxide levels after chronic morphine treatment. Intrathecal nonselective hydrogen peroxide scavenger phenyl-tert-N-butyl nitrone and the specific hydrogen peroxide catalyst catalase also abolished established morphine tolerance. Spinal dorsal horn astrocytes specifically expressed DAAO was significantly up-regulated, accompanying astrocyte hypertrophy after chronic morphine treatment. CONCLUSIONS: For the first time, the authors' result identify a novel spinal astroglial DAAO- hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.
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Authors | Nian Gong, Xin-Yan Li, Qi Xiao, Yong-Xiang Wang |
Journal | Anesthesiology
(Anesthesiology)
Vol. 120
Issue 4
Pg. 962-75
(Apr 2014)
ISSN: 1528-1175 [Electronic] United States |
PMID | 23928652
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Analgesics, Opioid
- Morphine
- Hydrogen Peroxide
- D-Amino-Acid Oxidase
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Topics |
- Analgesics, Opioid
(metabolism, pharmacology)
- Animals
- Astrocytes
(enzymology, metabolism)
- D-Amino-Acid Oxidase
(metabolism)
- Drug Tolerance
(physiology)
- Hydrogen Peroxide
(metabolism)
- Male
- Mice
- Morphine
(metabolism, pharmacology)
- Pain
(drug therapy)
- Rats
- Rats, Wistar
- Spinal Cord
(enzymology, metabolism)
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