(+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats.
(+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats.
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DOI：
10.1016/j.jpain.2012.02.005
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发表时间：
2012-05
期刊：
影响因子：
4
通讯作者：
Watkins, Linda R.
中科院分区：
文献类型：
--
作者：
Lewis, Susannah S.;Loram, Lisa C.;Hutchinson, Mark R.;Li, Chien-Ming;Zhang, Yingning;Maier, Steven F.;Huang, Yong;Rice, Kenner C.;Watkins, Linda R.
先前的工作表明，阿片类拮抗剂（-）-纳洛酮和非阿片类（+）-纳洛酮均抑制Toll样受体4（TLR 4）信号传导，并逆转慢性压迫性损伤后不久表达的神经性疼痛。目前的研究表明，TLR 4在另一种主要模型（脊神经结扎）中有助于神经性疼痛，并有助于长期建立（2-4个月）的神经性疼痛，而不仅仅是神经损伤后不久的疼痛。此外，皮下给药后（+）-纳洛酮的血浆水平分析表明，（+）-纳洛酮的药代动力学与（−）-纳洛酮相当，半衰期相对较短。这一发现解释了皮下（+）-纳洛酮产生的异常性疼痛逆转的快速起效和短持续时间。考虑到TLR 2最近也与神经性疼痛有关，用TLR 4或TLR 2、必要的共信号传导分子和报告基因转染的细胞系用于确定（+）-纳洛酮效应是否可以通过除了TLR 4之外的TLR 2的作用来解释。（+）-纳洛酮抑制TLR 4的信号传导，但不抑制TLR 2。这些研究为TLR 4广泛参与神经病理性疼痛提供了证据，无论是神经损伤后的早期还是数月后。此外，它们为TLR 4抑制剂（+）-纳洛酮作为治疗神经性疼痛的新候选物提供了进一步的支持。
Previous work demonstrated that both the opioid antagonist (−)-naloxone and the nonopioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2–4 mon) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-naloxone after subcutaneous administration indicate that (+)-naloxone has comparable pharmacokinetics to (−)-naloxone with a relatively short half-life. This finding accounts for the rapid onset and short duration of allodynia reversal produced by subcutaneous (+)-naloxone. Given that TLR2 has also recently been implicated in neuropathic pain, cell lines transfected with either TLR4 or TLR2, necessary co-signaling molecules, and a reporter gene were used to define whether (+)-naloxone effects could be accounted for by actions at TLR2 in addition to TLR4. (+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later. Additional, they provide further support for the TLR4 inhibitor (+)-naloxone as a novel candidate for the treatment of neuropathic pain.
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影响因子：
15.1
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
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：
3.3
作者：
Lewis, S. S.;Hutchinson, M. R.;Rezvani, N.;Loram, L. C.;Zhang, Y.;Maier, S. F.;Rice, K. C.;Watkins, L. R.
通讯作者：
Watkins, L. R.
影响因子：
2
作者：
Kim, KJ;Yoon, YW;Chung, JM
通讯作者：
Chung, JM
影响因子：
7.4
作者：
BENNETT, GJ;XIE, YK
通讯作者：
XIE, YK