Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4).
Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4).
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DOI：
10.1111/j.1460-9568.2008.06321.x
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发表时间：
2008-07
影响因子：
3.4
通讯作者：
Watkins, Linda R.
中科院分区：
文献类型：
--
作者：
Hutchinson, Mark R.;Zhang, Yingning;Brown, Kimberley;Coats, Benjamen D.;Shridhar, Mitesh;Sholar, Paige W.;Patel, Sonica J.;Crysdale, Nicole Y.;Harrison, Jacqueline A.;Maier, Steven F.;Rice, Kenner C.;Watkins, Linda R.
虽然活化的脊髓胶质细胞在神经病理性疼痛中起重要作用，但神经损伤如何激活胶质细胞仍存在争议。最近有人提出，在遗传学方法的基础上，Toll样受体4（TLR 4）可能是L5脊神经损伤后启动小胶质细胞激活的关键受体。目前的研究扩展了这一想法，表明TLR 4是维持坐骨神经慢性压迫性损伤（CCI）后神经性疼痛的关键。鞘内注射脂多糖衍生的TLR 4受体拮抗剂可逆转神经病理性疼痛。此外，（+）-纳洛酮、（+）-纳洛酮和（-）-纳洛酮，我们在此显示其在稳定转染的HEK 293-TLR 4和小胶质细胞系上都是TLR 4拮抗剂，在慢性输注后抑制神经性疼痛并完全逆转。慢性输注后脊髓的免疫组织化学分析显示，（+）-纳洛酮和（-））-纳洛酮抑制了CCI诱导的小胶质细胞活化，与神经性疼痛的逆转平行。总之，这些CCI数据支持这样的结论，即通过TLR 4的神经元-神经胶质信号传导不仅对于引发神经性疼痛很重要，如前所述，而且对于维持已建立的神经性疼痛也很重要。此外，这些研究表明，新的TLR 4拮抗剂（+）-纳洛酮和（-））-纳洛酮在多日施用后可各自完全逆转已建立的神经性疼痛。（+）-纳洛酮的这一结果具有潜在的临床意义。这是因为（+）-纳洛酮是一种拮抗剂，对产生镇痛作用的神经元上的（-）-阿片样物质选择性受体无活性。因此，这些数据表明（+）-阿片拮抗剂如（+）-纳洛酮在临床上可用于抑制神经胶质活化，而（-））-阿片激动剂抑制疼痛。
Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-))-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-))-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-))-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-))-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-))-opioid agonists suppress pain.
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影响因子：
5.3
作者：
Milligan, ED;O'Connor, KA;Watkins, LR
通讯作者：
Watkins, LR
影响因子：
7.4
作者：
Ledeboer, A;Sloane, EM;Watkins, LR
通讯作者：
Watkins, LR
影响因子：
5
作者：
Mika, Joanna;Osikowicz, Maria;Przewlocka, Barbara
通讯作者：
Przewlocka, Barbara
影响因子：
2.9
作者：
Milligan, ED;Mehmert, KK;Watkins, LR
通讯作者：
Watkins, LR
影响因子：
7.4
作者：
BENNETT, GJ;XIE, YK
通讯作者：
XIE, YK