Analgesic profile of intrathecal P2X3 antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats
Analgesic profile of intrathecal P2X3 antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats
复制标题
DOI：
10.1016/s0304-3959(02)00032-5
复制
发表时间：
2002-09-01
期刊：
影响因子：
7.4
通讯作者：
Lynch, K
中科院分区：
文献类型：
--
作者：
Honore, P;Kage, K;Lynch, K
细胞外三磷酸腺苷(ATP)作用于P2X离子亲和性受体，参与多种感觉过程。外源性三磷酸腺苷已被证明在动物和人类中都具有致过敏作用。研究的焦点一直集中在P2X(3)受体，因为它优先表达在伤害性C纤维上，其在疼痛处理中的意义被P2X(3)基因敲除小鼠的伤害性表型改变所支持。为了进一步研究P2X(3)受体激活在伤害性反应中的作用，我们观察了鞘内持续注射P2X(3)反义寡核苷酸7天的效果。大鼠后爪注射完全弗氏佐剂(CFA)、福尔马林或α-亚甲基三磷酸腺苷后，P2X(3)受体反义寡核苷酸处理可显著减少大鼠的伤害性行为。在炎性痛CFA模型中，反义治疗的抗痛敏作用与剂量相关。两种不同的P2X(3)反义寡核苷酸也有类似的作用。这些行为效应与背根神经节(DRG)中P2X(3)受体蛋白表达的减少显著相关。相反，背根神经节中P2X(3)受体蛋白表达的减少并不影响急性热痛敏卡拉胶模型的伤害性行为。P2X(3)受体反义寡核苷酸治疗也可显著减轻脊神经结扎后观察到的机械性超敏反应。总体而言，目前的数据表明，P2X(3)受体的激活有助于慢性炎症性和神经病理性疼痛状态的表达，这些形式的慢性疼痛的缓解可能通过选择性地阻断P2X(3)受体的表达或激活来实现。(C)2002年国际疼痛研究协会。爱思唯尔科学公司出版。版权所有。
Extracellular adenosine triphosphate (ATP), acting at P2X ionotropic receptors, is implicated in numerous sensory processes. Exogenous ATP has been shown to be algogenic in both animals and humans. Research focus has been directed towards the P2X(3) receptor, as it is preferentially expressed on nociceptive C-fibers and its implication in pain processing is supported by an altered nociceptive phenotype in P2X(3) knock-out mice. In order to further characterize the role of P2X(3) receptor activation in nociception, we evaluated the effects of continuous intrathecal administration of P2X(3) antisense oligonucleotides for 7 days in the rat. P2X(3) receptor antisense oligonucleotide treatment significantly decreased nociceptive behaviors observed after injection of complete Freund's adjuvant (CFA), formalin or alphabeta-methylene ATP into the rat's hind paw. The anti-hyperalgesic effects of the antisense treatment in the CFA model of inflammatory pain were dose related. Similar effects were observed with two distinct P2X(3) antisense oligonucleotides. These behavioral effects were significantly correlated with a decrease in P2X(3) receptor protein expression in the dorsal root ganglia (DRG). In contrast, a decrease in P2X(3) receptor protein expression in the DRG did not affect nociceptive behavior in the carrageenan model of acute thermal hyperalgesia. P2X(3) receptor antisense oligonucleotide treatment also significantly reduced mechanical allodynia observed after spinal nerve ligation. Overall, the present data demonstrate that activation of P2X(3) receptors contribute to the expression of chronic inflammatory and neuropathic pain states and that relief form these forms of chronic pain might be achieved by selective blockade of P2X(3) receptor expression or activation. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.