Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: a novel therapy for neuropathic pain.
Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: a novel therapy for neuropathic pain.
复制标题
DOI：
10.1523/jneurosci.3447-09.2009
复制
发表时间：
2009-11-04
期刊：
影响因子：
--
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Loram LC;Harrison JA;Sloane EM;Hutchinson MR;Sholar P;Taylor FR;Berkelhammer D;Coats BD;Poole S;Milligan ED;Maier SF;Rieger J;Watkins LR
先前对外周免疫细胞的研究表明，腺苷 2A 受体 (A2AR) 的激活会减少促炎细胞因子的释放，并增加强效抗炎细胞因子白细胞介素 10 (IL-10) 的释放。鉴于越来越多的文献支持神经胶质促炎细胞因子对神经性疼痛有重要影响，并且 IL-10 可以抑制此类疼痛，我们使用慢性缩窄性损伤 (CCI) 模型评估了鞘内 (i.t.) 施用 A2AR 激动剂对神经性疼痛的影响。一个单独的it。与假手术相比，CCI 后 10-14 天注射 A2AR 激动剂 ATL313 或 CGS21680 产生了机械异常性疼痛和热痛觉过敏的长期逆转，持续至少 4 周。这两种药物都没有改变假手术对照的伤害性反应。 A2AR 拮抗剂 (ZM241385) 联合给药。与ATL313一起使用可消除ATL313对神经病引起的异常性疼痛大鼠的作用，但在没有A2AR激动剂的情况下对异常性疼痛没有影响。在单次 i.t. 后 1 周和 4 周，ATL313 减弱了 CCI 诱导的 L4-L6 脊髓段小胶质细胞和星形胶质细胞脊髓激活标记物的上调。 ATL313 管理。经t给药的中和IL-10抗体暂时消除了 ATL313 对神经性疼痛的作用。此外，从腰部收集的脑脊液细胞中，IL-10 mRNA 显着升高。 i.t. 后 A2AR 的激活通过增加中枢神经系统免疫活性细胞中的IL-10，给药可能是治疗神经性疼痛的一种新的治疗方法。
Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A2AR) decrease pro-inflammatory cytokine release and increase release of the potent anti-inflammatory cytokine, interleukin-10 (IL-10). Given the growing literature supporting that glial proinflammatory cytokines importantly contribute to neuropathic pain, and that IL-10 can suppress such pain, we evaluated the effects of intrathecally (i.t.) administered A2AR agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single i.t. injection of the A2AR agonists ATL313 or CGS21680, 10-14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 wk. Neither drug altered the nociceptive responses of sham-operated controls. An A2AR antagonist (ZM241385) co-administered i.t. with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia, but had no effect on allodynia in the absence of the A2AR agonist. ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4-L6 spinal cord segments both 1 wk and 4 wk after a single i.t. ATL313 administration. Neutralizing IL-10 antibodies administered i.t. transiently abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region. Activation of A2ARs following i.t. administration may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.