D-Amino acid oxidase (DAAO), a FAD-dependent peroxisomal flavoenzyme that catalyzes oxidation of D-amino acids to hydrogen peroxide, is distributed in the spinal cord almost exclusively expressed within astrocytes. The present study aims to explore potential contributions of spinal DAAO to the development of bone cancer pain and morphine tolerance to analgesia. Tibia inoculation of carcinoma cells produced mechanical allodynia (but not heat hyperalgesia), in synchronous with induction of DAAO expression and DAAO enzymatic activity, as well as activation of spinal astrocytes marked by GFAP. Subcutaneous and intrathecal injection of the specific DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) blocked mechanical allodynia in a dose- and time-dependent manner in tumor-bearing rats, with maximum inhibition of 40-50 %. Multi-daily intrathecal injections of the DAAO gene silencer siRNA/DAAO also yielded anti-allodynic effects by approximately 40 % and the analgesia remained for at least 6 days. Subcutaneous injection of CBIO suppressed the production of spinal hydrogen peroxide and GFAP expression. 7-Day multiple bi-daily injections of CBIO produced anti-allodynia without inducing self-tolerance to analgesia or cross-tolerance to morphine, and concurrent injections of CBIO with morphine produced apparent additive anti-allodynia and completely prevented morphine tolerance in behaviors and spinal expression of μ-opioid receptors. Our results provide the first evidence that spinal DAAO contributes to the development of morphine tolerance to analgesia and bone cancer pain accounting for 40-50 % pain status, probably via production of hydrogen peroxide leading to activation of astrocytes. The unique characterizations of DAAO inhibitors make them a potential for the treatment of cancer pain when they are administered alone or in combination with morphine.

译文

D-氨基酸氧化酶 (DAAO) 是一种FAD依赖性过氧化物酶体黄素酶,可催化D-氨基酸氧化为过氧化氢,分布在脊髓中,几乎仅在星形胶质细胞内表达。本研究旨在探讨脊髓DAAO对骨癌疼痛和吗啡镇痛耐受性的潜在贡献。与DAAO表达和DAAO酶活性的诱导以及GFAP标记的脊髓星形胶质细胞的激活同步,胫骨接种癌细胞会产生机械性异常性疼痛 (但不会产生热痛觉过敏)。皮下和鞘内注射特定的DAAO抑制剂CBIO (5-氯-苯并 [d]isoxazol-3-ol) 以剂量和时间依赖性方式阻断荷瘤大鼠的机械性异常性疼痛,最大抑制作用为40-50%。DAAO基因沉默子siRNA/DAAO的多天鞘内注射也产生了约40% 的抗异常性作用,镇痛作用保持至少6天。皮下注射CBIO抑制了脊髓过氧化氢的产生和GFAP的表达。7天多次双日注射CBIO可产生抗异常性疼痛,而不会引起对镇痛的自我耐受性或对吗啡的交叉耐受性,同时注射CBIO与吗啡可产生明显的累加性抗异常性疼痛,并完全阻止行为和行为中的吗啡耐受性。μ 阿片受体的脊髓表达。我们的结果提供了第一个证据,表明脊髓DAAO有助于吗啡对镇痛和骨癌疼痛的耐受性的发展,这可能是通过产生过氧化氢导致星形胶质细胞活化而导致的40-50% 疼痛状态。DAAO抑制剂的独特特征使其成为单独或与吗啡联合使用时治疗癌症疼痛的潜力。

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