title: Contributions of spinal D-amino acid oxidase to chronic morphine-induced hyperalgesia.
abstract: Spinal D-amino acid oxidase (DAAO) is an FAD-dependent peroxisomal flavoenzyme which mediates the conversion of neutral and polar D-amino acids (including D-serine) to the corresponding α-keto acids, and simultaneously produces hydrogen peroxide and ammonia. This study has aimed to explore the potential contributions of spinal DAAO and its mediated hydrogen peroxide/D-serine metabolism to the development of morphine-induced hyperalgesia. Bi-daily subcutaneous injections of morphine to mice over 7 days induced thermal hyperalgesia as measured by both the hot-plate and tail-immersion tests, and spinal astroglial activation with increased spinal gene expression of DAAO, glial fibrillary acidic protein (GFAP) and pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)). Subcutaneous injections of the potent DAAO inhibitor CBIO (5-chloro-benzo[D]isoxazol-3-ol) prevented and reversed the chronic morphine-induced hyperalgesia. CBIO also inhibited both astrocyte activation and the expression of pro-inflammatory cytokines. Intrathecal injection of the hydrogen peroxide scavenger PBN (phenyl-N-tert-butylnitrone) and of catalase completely reversed established morphine hyperalgesia, whereas subcutaneous injections of exogenous D-serine failed to alter chronic morphine-induced hyperalgesia. These results provided evidence that spinal DAAO and its subsequent production of hydrogen peroxide rather than the D-serine metabolism contributed to the development of morphine-induced hyperalgesia.
authors: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors: Shuai
authors: S
authors: Ma
authors: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors: Xin-Yan
authors: XY
authors: Li
authors: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors: Nian
authors: N
authors: Gong
authors: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yxwang@sjtu.edu.cn.
authors: Yong-Xiang
authors: YX
authors: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000378:metabolism*; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy* / Q000201:enzymology*; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D003605:D-Amino-Acid Oxidase
keywords: CBIO (5-chloro-benzo[d]isoxazol-3-ol); Morphine-induced hyperalgesia; Spinal cord; d-Amino acid oxidase (DAAO)