The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1αβ knockout mice
The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1αβ knockout mice
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DOI：
10.1016/j.bbr.2009.05.018
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发表时间：
2009-12-01
影响因子：
2.7
通讯作者：
Jarvis, Michael F.
中科院分区：
文献类型：
--
作者：
Honore, Prisca;Donnelly-Roberts, Diana;Jarvis, Michael F.
促炎症细胞因子白介素1β(IL-1β)参与炎症过程和伤害性神经传递。激活P2X7受体是三磷酸腺苷刺激巨噬细胞和小胶质细胞迅速成熟和释放IL-1β的机制。最近，选择性的P2X7受体拮抗剂在动物模型中被证明可以减轻炎症性和神经病理性疼痛。然而，这些止痛作用的机制尚不清楚。目前的研究表征了一种结构新颖的P2X7拮抗剂的药理和抗伤害效应。A-839977(IC_(50)=20-150 nM)可阻断BzATP诱导的重组人、大鼠和小鼠P2X7受体的钙内流。A-839977还有效地阻断了激动剂诱导的人THP-1细胞摄取Yo-Pro和释放IL-1β。全身应用A-839977可剂量依赖性地减少足底注射完全弗氏佐剂(CIA)所产生的热痛觉过敏(ED_(50)=100umol/kg，i.p.)。在老鼠身上。A-839977对野生型小鼠炎性疼痛的CIA模型(ED50=40mU/kg，ip)也有较强的抗痛敏作用，但在IL-1αβ基因敲除小鼠中，A-839977的抗痛过敏作用完全消失。这些数据表明，选择性阻断体内的P2X7受体在炎症性疼痛动物模型中产生显著的抗伤害作用，并提示P2X7受体拮抗剂在小鼠炎症性疼痛模型中的抗痛敏作用是通过阻断IL-1β的释放而实现的。(C)2009爱思唯尔B.V.保留所有权利。
The pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) has been implicated in both inflammatory processes and nociceptive neurotransmission. Activation of P2X7 receptors is the mechanism by which ATP stimulates the rapid maturation and release of IL-1 beta from macrophages and microglial cells. Recently, selective P2X7 receptor antagonists have been shown to reduce inflammatory and neuropathic pain in animal models. However, the mechanisms underlying these analgesic effects are unknown. The present studies characterize the pharmacology and antinociceptive effects of a structurally novel P2X7 antagonist. A-839977 potently (IC50 = 20-150 nM) blocked BzATP-evoked calcium influx at recombinant human, rat and mouse P2X7 receptors. A-839977 also potently blocked agonist-evoked YO-PRO uptake and IL-1 beta release from differentiated human THP-1 cells. Systemic administration of A-839977 dose-dependently reduced thermal hyperalgesia produced by intraplantar administration of complete Freund's adjuvant (CIA) (ED50 = 100 mu mol/kg, i.p.) in rats. A-839977 also produced robust antihyperalgesia in the CIA model of inflammatory pain in wild-type mice (ED50 = 40 mu mol/kg, i.p.), but the anti hyperalgesic effects of A-839977 were completely absent in IL-1 alpha beta knockout mice. These data demonstrate that selective blockade of P2X7 receptors in vivo produces significant antinociception in animal models of inflammatory pain and suggest that the anti hyperalgesic effects of P2X7 receptor blockade in an inflammatory pain model in mice are mediated by blocking the release of IL-1 beta. (C) 2009 Elsevier B.V. All rights reserved.