Interactions of the potent D-amino acid oxidase inhibitor CBIO with morphine in pain and tolerance to analgesia
Interactions of the potent D-amino acid oxidase inhibitor CBIO with morphine in pain and tolerance to analgesia
复制标题
强效 D-氨基酸氧化酶抑制剂 CBIO 与吗啡在疼痛和镇痛耐受中的相互作用
DOI：
10.1016/j.neuropharm.2012.04.030
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发表时间：
2012-09-01
影响因子：
4.7
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Gong, Nian;Wang, Yan-Chao;Wang, Yong-Xiang
一系列利用基因突变和沉默技术以及化学生物学技术的实验表明，脊髓D-氨基酸氧化酶（DAAO）有助于中枢敏化介导的慢性疼痛的发生，可能是治疗慢性疼痛的潜在分子靶点。 DAAO 抑制剂目前正在进行治疗慢性神经性疼痛的临床研究。本研究主要在福尔马林试验中检查吗啡和 DAAO 抑制剂 CBIO（5-氯苯并[d]异恶唑-3-醇）在疼痛和镇痛耐受性方面的相互作用。在急性伤害感受环境（福尔马林急性期伤害感受、热板试验和尾部浸没试验）和福尔马林引起的强直性疼痛中，皮下注射 CBIO 与吗啡在镇痛方面以累加方式发生急性相互作用。每天两次皮下注射 7 天的 CBIO 不会产生对镇痛的自我耐受性或对吗啡的交叉耐受性，而皮下注射 7 天的吗啡会诱导对镇痛的自我耐受性，但不会对 CBIO 产生交叉耐受性。更重要的是，在福尔马林引起的急性期伤害性疼痛和强直期疼痛中，皮下联合给药甚至单剂量CBIO完全预防或逆转吗啡对镇痛的耐受性（通过单剂量或吗啡的剂量反应曲线显示）。这些结果首次确定了DAAO是介导吗啡耐受的有效分子，同时阐明了CBIO探索的吗啡与DAAO抑制剂之间复杂的相互作用，为DAAO抑制剂与吗啡联合用于临床治疗疼痛提供了药理学基础。 (C) 2012 Elsevier Ltd. 保留所有权利。
A series of experiments using technologies of gene mutation and silencing as well as chemical biology have demonstrated that spinal D-amino acid oxidase (DAAO) contributes to the development of central sensitization-mediated chronic pain and might be a potential molecular target for the treatment of chronic pain. DAAO inhibitors are now under clinical investigations for the management of chronic neuropathic pain. This study examined the interactions between morphine and the DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) in pain and analgesia tolerance mainly in the formalin test. Given subcutaneously CBIO acutely interacted with morphine in analgesia in an additive manner both in the acute nociception settings (the formalin acute phase nociception, hot-plate test and tail immersion test) and in formalin-induced tonic pain. Bi-daily exposure of CBIO given subcutaneously for 7 days did not produce self-tolerance to analgesia or cross-tolerance to morphine whereas 7-day subcutaneous morphine induced self-tolerance to analgesia but not cross-tolerance to CBIO. More importantly, subcutaneous co-administrations or even single dose of CBIO completely prevented or reversed morphine tolerance to analgesia (exhibited by a single dose or a dose response curve of morphine) in both formalin-induced acute phase nociception and tonic phase pain. These results, for the first time, identified DAAO as an efficacious molecule mediating morphine tolerance, in addition to clarifying the complex interactions between morphine and DAAO inhibitors probed by CBIO, and provided a pharmacological basis for DAAO inhibitors in combination with morphine to clinically manage pain. (C) 2012 Elsevier Ltd. All rights reserved.