Contributions of spinal D-amino acid oxidase to bone cancer pain
Contributions of spinal D-amino acid oxidase to bone cancer pain
复制标题
脊髓 D-氨基酸氧化酶对骨癌疼痛的作用
DOI：
10.1007/s00726-012-1390-z
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发表时间：
2012-11-01
期刊：
影响因子：
3.5
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Huang, Jin-Lu;Chen, Xiao-Ling;Wang, Yong-Xiang
D-氨基酸氧化酶(DAAO)是一种依赖FAD的过氧化物黄素酶，催化D-氨基酸氧化为过氧化氢，分布于脊髓，几乎仅在星形胶质细胞中表达。本研究旨在探讨脊髓DAAO在骨癌疼痛和吗啡耐受镇痛中的潜在作用。接种肿瘤细胞的胫骨产生机械性痛觉过敏(而不是热痛敏)，同时诱导DAAO的表达和DAAO酶的活性，并以GFAP标记的脊髓星形胶质细胞激活。皮下和鞘内注射特异性DAAO抑制剂CBIO(5-氯苯并[d]异恶唑-3-醇)以剂量和时间依赖的方式阻断荷瘤大鼠的机械性痛觉过敏，最大抑制率为40-50%。鞘内多次注射DAAO基因沉默剂siRNA/DAAO也可产生约40%的抗痛觉过敏效果，且镇痛作用持续至少6天。皮下注射CBIO可抑制脊髓过氧化氢的产生和GFAP的表达。7d连续两次注射CBIO可产生抗痛敏作用，但不会引起自身的镇痛耐受或对吗啡的交叉耐受，CBIO与吗啡同时注射可产生明显的相加抗痛觉作用，并可完全阻止吗啡耐受行为和mU-阿片受体在脊髓中的表达。我们的结果首次证明脊髓DAAO参与了吗啡镇痛耐受性的形成，骨癌疼痛占疼痛状态的40%-50%，可能是通过产生过氧化氢导致星形胶质细胞的激活。DAAO抑制剂的独特特性使其在单独或与吗啡联合应用时具有治疗癌症疼痛的潜力。
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 mu-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.