Identification of a Novel Spinal Dorsal Horn Astroglial d-Amino Acid Oxidase-Hydrogen Peroxide Pathway Involved in Morphine Antinociceptive Tolerance
Identification of a Novel Spinal Dorsal Horn Astroglial d-Amino Acid Oxidase-Hydrogen Peroxide Pathway Involved in Morphine Antinociceptive Tolerance
复制标题
新型脊髓背角星形胶质细胞 D-氨基酸氧化酶 - 参与吗啡镇痛耐受的过氧化氢途径的鉴定
DOI：
10.1097/aln.0b013e3182a66d2a
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发表时间：
2014-04-01
期刊：
影响因子：
8.8
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Gong, Nian;Li, Xin-Yan;Wang, Yong-Xiang
背景资料：D-氨基酸氧化酶（DAAO）是一种黄素腺嘌呤二核苷酸依赖性过氧化物酶体黄素酶，其几乎仅在脊髓中的星形胶质细胞内表达。DAAO催化d-氨基酸氧化成过氧化氢，过氧化氢是一种稳定且活性较低的活性氧物质，并且可能代表活性氧物质的最终形式。本研究验证了脊髓星形胶质细胞DAAO-过氧化氢通路在吗啡抗伤害性tolerance.Methods的发展中起着重要作用的假设：大鼠和小鼠福尔马林，热板，甩尾实验，和脊髓DAAO表达和过氧化氢水平进行了测定。结果：皮下注射和鞘内注射DAAO抑制剂，包括5-chloro-benzo[d] isoxazole-3-ol、AS 057278和苯甲酸钠，在福尔马林、热板和尾浸试验中均能完全预防和逆转吗啡镇痛耐受，且与其DAAO抑制活性呈正相关。鞘内基因沉默剂，小干扰RNA/DAAO和小发夹RNA/DAAO，几乎完全阻止吗啡耐受。鞘内注射5-氯-苯并[d]异恶唑-3-醇和小干扰RNA/DAAO完全防止慢性吗啡治疗后脊髓过氧化氢水平升高。鞘内非选择性过氧化氢清除剂苯基叔丁基硝酮和特定的过氧化氢催化剂过氧化氢酶也废除了建立吗啡耐受。慢性吗啡处理后，脊髓背角星形胶质细胞特异性表达DAAO的表达显著上调，伴随着星形胶质细胞肥大。作者的结果首次确定了一种新的脊髓星形胶质细胞DAAO-过氧化氢通路，该通路在吗啡抗伤害耐受的启动和维持中起关键作用，并提示该通路在吗啡耐受和慢性疼痛的管理中具有潜在的效用。
Background: d-Amino acid oxidase (DAAO) is a flavin adenine dinucleotide-dependent peroxisomal flavoenzyme which is almost exclusively expressed within astrocytes in the spinal cord. DAAO catalyzes oxidation of d-amino acids to hydrogen peroxide, which is a stable and less active reactive oxygen species, and may represent a final form of reactive oxygen species. This study tested the hypothesis that the spinal astroglial DAAO-hydrogen peroxide pathway plays an important role in the development of morphine antinociceptive tolerance.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.