Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado-Boulder, Boulder, CO 80309-0345, United States.
Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado-Boulder, Boulder, CO 80309-0345, United States.
Brain Behav Immun. 2018 Mar;69:470-479. doi: 10.1016/j.bbi.2018.01.005. Epub 2018 Jan 31.
Central neuropathic pain is a debilitating outcome of spinal cord injury (SCI) and current treatments to alleviate this pain condition are ineffective. A growing body of literature suggests that activating adenosine A receptors (ARs) decreases the production of proinflammatory cytokines and increases the production of anti-inflammatory cytokines. Here, the effect of administering intrathecal AR agonists on central neuropathic pain was measured using hindpaw mechanical allodynia in a rat model of SCI termed spinal neuropathic avulsion pain (SNAP). Other models of SCI cause extensive damage to the spinal cord, resulting in paralysis and health problems. SNAP rats with unilateral low thoracic (T13)/high lumbar (L1) dorsal root avulsion develop below-level bilateral allodynia, without concomitant motor or health problems. A single intrathecal injection of the AR agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680) reversed SCI-induced allodynia for at least 6 weeks. The reversal is likely in part mediated by interleukin (IL)-10, as intrathecally administering neutralizing IL-10 antibodies 1 week after CGS21680 abolished the anti-allodynic effect of CGS21680. Dorsal spinal cord tissue from the ipsilateral site of SCI (T13/L1) was assayed 1 and 6 weeks after CGS21680 for IL-10, CD11b, and tumor necrosis factor (TNF) gene expression. CGS21680 treatment did not change IL-10 gene expression but did significantly decrease CD11b and TNF gene expression at both timepoints. A second AR agonist, 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313), was also able to significantly prevent and reverse SCI-induced allodynia for several weeks after a single intrathecal injection, providing converging lines of evidence of AR involvement. The enduring pain reversal after a single intrathecal injection of AR agonists suggests that AR agonists could be exciting new candidates for treating SCI-induced central neuropathic pain.
中枢性神经病理性疼痛是脊髓损伤 (SCI) 的一种使人虚弱的结果，目前用于缓解这种疼痛状况的治疗方法无效。越来越多的文献表明，激活腺苷 A 受体 (AR) 可减少促炎细胞因子的产生并增加抗炎细胞因子的产生。在这里，通过 SCI 大鼠模型（称为脊髓神经性撕脱痛 (SNAP)）中的后爪机械性感觉过敏来测量鞘内 AR 激动剂对中枢性神经病理性疼痛的影响。其他 SCI 模型会对脊髓造成广泛的损伤，导致瘫痪和健康问题。单侧胸 13 高腰 1 背根撕脱的 SNAP 大鼠会发展出下位双侧感觉过敏，而没有伴随运动或健康问题。单次鞘内注射 AR 激动剂 2-（2-羧乙基）苯乙氨基-5'-N-乙基羧酰胺腺苷 HCl（CGS21680）可至少逆转 SCI 引起的感觉过敏 6 周。这种逆转可能部分是由白细胞介素 (IL)-10 介导的，因为在 CGS21680 后 1 周鞘内给予中和 IL-10 抗体可消除 CGS21680 的抗感觉过敏作用。在 CGS21680 后 1 和 6 周，对同侧 SCI（T13/L1）部位的脊髓背角组织进行 IL-10、CD11b 和肿瘤坏死因子 (TNF) 基因表达的检测。CGS21680 处理并未改变 IL-10 基因表达，但在两个时间点均显著降低 CD11b 和 TNF 基因表达。第二种 AR 激动剂，4-（3-（6-氨基-9-（5-环丙基羰基-3,4-二氢四氢呋喃-2-基）-9H-嘌呤-2-基）-2-炔基）哌啶-1-羧酸甲酯（ATL313），也能够在单次鞘内注射后数周内显著预防和逆转 SCI 引起的感觉过敏，提供了 AR 参与的证据。单次鞘内注射 AR 激动剂后持久的疼痛逆转表明，AR 激动剂可能是治疗 SCI 引起的中枢性神经病理性疼痛的令人兴奋的新候选药物。
