Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling
Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling
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DOI：
10.1038/npp.2016.131
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发表时间：
2017-02-01
影响因子：
7.6
通讯作者：
Murphy, Anne Z.
中科院分区：
文献类型：
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作者：
Eidson, Lori N.;Inoue, Kiyoshi;Murphy, Anne Z.
阿片类药物耐受性和成瘾的可能性是与疼痛管理相关的重大负担，但其确切的潜在机制和预防仍然难以捉摸。免疫信号导致阿片类药物疗效下降，我们最近证实Toll样受体4(TLR4)介导的中脑导水管周围灰质(PAG)神经炎症驱动耐受。肿瘤坏死因子(TNF)是TLR4信号的产物，它促进炎症并促进谷氨酸能信号转导，而谷氨酸能信号是阿片耐受的关键成分。因此，我们假设TLR4介导的阿片耐受需要肿瘤坏死因子信号。通过慢病毒载体注射在大鼠PAG中表达显性负性肿瘤坏死因子多肽以隔离可溶性肿瘤坏死因子(SoITNF)，我们证明了solTNF介导了TLR4信号诱导的吗啡耐受，刺激了神经炎症(增加了IL-1β和TLR4mRNA)，并破坏了谷氨酸的再摄取(降低了GLT-1和GLAST mRNA)。我们进一步证明了经系统注射的脑部聚乙二醇化的抗肿瘤坏死因子多肽XPro1595的有效性，以正常化吗啡诱导的中枢神经系统炎症和吗啡和内毒素诱导的谷氨酸运输的变化，有效地呈现出吗啡镇痛和消除耐受的效果。我们的发现为预防阿片类药物诱导的免疫信号、耐受和成瘾提供了一个新的药理靶点。
Opioid tolerance and the potential for addiction is a significant burden associated with pain management, yet its precise underlying mechanism and prevention remain elusive. Immune signaling contributes to the decreased efficacy of opioids, and we recently demonstrated that Toll-like receptor 4 (TLR4)-mediated neuroinflammation in the periaqueductal gray (PAG) drives tolerance. Tumor necrosis factor (TNF), a product of TLR4 signaling, promotes inflammation and facilitates glutamatergic signaling, key components of opioid tolerance. Therefore, we hypothesize that TLR4-mediated opioid tolerance requires TNF signaling. By expression of a dominant-negative TNF peptide via lentiviral vector injection in rat PAG to sequester soluble TNF (soITNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1 beta and TLR4 mRNA), and disrupts glutamate reuptake (decreased GLT-1 and GLAST mRNA). We further demonstrate the efficacy of the brain-permeant PEGylated version of the anti-solTNF peptide, XPro1595, injected systemically, to normalize morphine-induced CNS neuroinflammation and morphine- and endotoxin-induced changes in glutamate transport, effectively presenting the efficacy of morphine analgesia and eliminating tolerance. Our findings provide a novel pharmacological target for the prevention of opioid-induced immune signaling, tolerance, and addiction.