Systemic administration of an alpha-7 nicotinic acetylcholine agonist reverses neuropathic pain in male Sprague Dawley rats.
Systemic administration of an alpha-7 nicotinic acetylcholine agonist reverses neuropathic pain in male Sprague Dawley rats.
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DOI：
10.1016/j.jpain.2012.08.009
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发表时间：
2012-12
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;Taylor FR;Strand KA;Maier SF;Speake JD;Jordan KG;James JW;Wene SP;Pritchard RC;Green H;Van Dyke K;Mazarov A;Letchworth SR;Watkins LR
α-7烟碱型乙酰胆碱受体(α7nAChR)激动剂可减轻临床前模型中的疼痛和炎症。这项研究测试了全身应用α7nAChR激动剂是否可以减轻神经病理性疼痛和相关的免疫介导的促炎作用。对雄性SD大鼠坐骨神经慢性缩窄性损伤(CCI)或假手术前后的后爪机械刺激反应阈值进行了检测。术后10~14d植入含α7nAChR选择性激动剂TC-7020型渗透微泵。TC-7020(1、3和10 mg/kg/d；S.C.)显著减轻CCI所致的痛觉异常，持续2周。2周后收集脊髓，在同侧L4-L6背角内检测小胶质细胞和星形胶质细胞的激活标志物。此外，对同侧L4-5背根节(DRGs)进行神经元损伤和卫星细胞激活标记。TC-7020对CCI诱导的中枢神经胶质细胞激活标志物没有抑制作用，即使TC-7020对血脑屏障有轻微的通透性。TC-7020可下调激活转录因子3(ATF3)的整合密度，但不影响ATF阳性细胞数。TC-7020还下调CCI影响的DRG中的磷酸化细胞外信号激酶(p-ERK)和卫星细胞的激活。因此，全身性α7nAChR激动剂可能通过减少周围神经元损伤和免疫细胞激活而有效地治疗神经病理性疼痛。这些研究表明，具有部分血脑屏障通透性的α7烟碱型乙酰胆碱受体激动剂TC-7020可以逆转大鼠神经病理性疼痛，可能是通过减轻背根节和/或坐骨神经损伤部位的炎症来实现的。
Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists attenuate pain and inflammation in preclinical models. This study tested whether systemic delivery of an α7 nAChR agonist attenuates neuropathic pain and associated immune-mediated pro-inflammation. Hind paw response thresholds to mechanical stimuli in male Sprague Dawley rats were assessed before and after sciatic chronic constriction injury (CCI) or sham surgery. Osmotic mini-pumps containing TC-7020, an α7 nAChR selective agonist, were implanted 10 to 14 days after surgery. TC-7020 (1, 3, and 10 mg/kg/d; s.c.) significantly attenuated CCI-induced allodynia, which lasted through 2 weeks of test compound administration. Spinal cords were collected after 2 weeks and processed for microglial and astrocyte activation markers within the ipsilateral L4-L6 dorsal horn. In addition, ipsilateral L4-5 dorsal root ganglia (DRGs) were processed for neuronal injury and satellite cell activation markers. CCI-induced central glial cell activation markers were not suppressed by TC-7020, even though TC-7020 is mildly blood-brain barrier permeable. However, TC-7020 downregulated the integrated density of activation transcription factor 3 (ATF3) but not the number of ATF positive cells. TC-7020 also downregulated phosphorylated extracellular signal kinase (p-ERK) and satellite cell activation in the CCI-affected DRGs. Therefore, systemic α7 nAChR agonist may be effective in treating neuropathic pain via reducing neuronal injury and immune cells activation occurring in the periphery. These studies demonstrated that TC-7020, an alpha7 nicotinic acetylcholine receptor agonist with partial blood-brain barrier permeability, reversed neuropathic pain in rats, likely via attenuation of inflammation in the DRG and/or the site of sciatic injury.
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影响因子：
8
作者：
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通讯作者：
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影响因子：
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影响因子：
2.7
作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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