D-Amino acid oxidase-mediated increase in spinal hydrogen peroxide is mainly responsible for formalin-induced tonic pain
D-Amino acid oxidase-mediated increase in spinal hydrogen peroxide is mainly responsible for formalin-induced tonic pain
复制标题
D-氨基酸氧化酶介导的脊髓过氧化氢增加是福尔马林引起的强直性疼痛的主要原因
DOI：
10.1111/j.1476-5381.2011.01680.x
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发表时间：
2012-03-01
影响因子：
7.3
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
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作者：
Lu, Jin-Miao;Gong, Nian;Wang, Yong-Xiang
研究背景与目的脊髓活性氧簇(ROS)在慢性疼痛中起重要作用。D-氨基酸氧化酶(DAAO)氧化D-氨基酸，如D-丝氨酸，形成副产物过氧化氢，而不产生其他ROS。DAAO抑制剂对紧张性疼痛、神经性疼痛和癌症疼痛具有特效的止痛药作用。本研究探讨了脊髓过氧化氢在疼痛中的作用以及DAAO抑制剂的镇痛作用机制。本研究测定了实验性阿普罗福林诱导的疼痛行为和脊髓过氧化氢水平。KEY结果足爪注射福尔马林使脊髓过氧化氢增加，同时增强紧张性疼痛；两者均被I.T.有效地阻止。氟柠檬酸盐，一种选择性星形胶质细胞代谢抑制剂。系统给予有效的DAAO抑制剂CBIO(5-氯苯并[d]异恶唑-3-醇)可阻断脊髓DAAO酶的活性，并以剂量依赖的方式特异性地预防福尔马林诱导的紧张性疼痛。虽然CBIO最大限度地抑制了62%的紧张性疼痛，但它完全阻止了脊髓过氧化氢的增加。IT。过氧化氢酶是一种专用于分解过氧化氢的酶，可以完全耗尽脊髓过氧化氢，并可防止65%的福尔马林引起的紧张性疼痛。系统给予ROS清除剂PBN(苯基-N-叔丁基硝酮)也可抑制福尔马林引起的紧张性疼痛和脊髓过氧化氢的增加。肌肉注射可增强福尔马林引起的紧张性疼痛。外源过氧化氢。CBIO不增加脊髓D-丝氨酸水平，而I.T.D-丝氨酸不改变福尔马林引起的紧张性疼痛或CBIO的镇痛效应。结论和应用脊髓过氧化氢是福尔马林引起的疼痛的特异性和主要原因，DAAO抑制剂通过阻断脊髓过氧化氢的产生而产生镇痛作用，而不是与脊髓D-丝氨酸相互作用。
BACKGROUND AND PURPOSESpinal reactive oxygen species (ROS) are critically involved in chronic pain. D-Amino acid oxidase (DAAO) oxidizes d-amino acids such as D-serine to form the byproduct hydrogen peroxide without producing other ROS. DAAO inhibitors are specifically analgesic in tonic pain, neuropathic pain and cancer pain. This study examined the role of spinal hydrogen peroxide in pain and the mechanism of the analgesic effects of DAAO inhibitors.EXPERIMENTAL APPROACHFormalin-induced pain behaviours and spinal hydrogen peroxide levels were measured in rodents.KEY RESULTSFormalin injected into the paw increased spinal hydrogen peroxide synchronously with enhanced tonic pain; both were effectively prevented by i.t. fluorocitrate, a selective astrocyte metabolic inhibitor. Given systemically, the potent DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) blocked spinal DAAO enzymatic activity and specifically prevented formalin-induced tonic pain in a dose-dependent manner. Although CBIO maximally inhibited tonic pain by 62%, it completely prevented the increase in spinal hydrogen peroxide. I.t. catalase, an enzyme specific for decomposition of hydrogen peroxide, completely depleted spinal hydrogen peroxide and prevented formalin-induced tonic pain by 65%. Given systemically, the ROS scavenger PBN (phenyl-N-tert-butylnitrone) also inhibited formalin-induced tonic pain and increase in spinal hydrogen peroxide. Formalin-induced tonic pain was potentiated by i.t. exogenous hydrogen peroxide. CBIO did not increase spinal D-serine level, and i.t. D-serine did not alter either formalin-induced tonic pain or CBIO's analgesic effect.CONCLUSIONS AND IMPLICATIONSSpinal hydrogen peroxide is specifically and largely responsible for formalin-induced pain, and DAAO inhibitors produce analgesia by blocking spinal hydrogen peroxide production rather than interacting with spinal D-serine.