Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae.
Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae.
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DOI：
10.1016/j.neuroscience.2014.09.020
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发表时间：
2014-11-07
期刊：
影响因子：
3.3
通讯作者：
Watkins, L. R.
中科院分区：
文献类型：
--
作者：
Grace, P. M.;Ramos, K. M.;Rodgers, K. M.;Wang, X.;Hutchinson, M. R.;Lewis, M. T.;Morgan, K. N.;Kroll, J. L.;Taylor, F. R.;Strand, K. A.;Zhang, Y.;Berkelhammer, D.;Huey, M. G.;Greene, L. I.;Cochran, T. A.;Yin, H.;Barth, D. S.;Johnson, K. W.;Rice, K. C.;Maier, S. F.;Watkins, L. R.
中枢神经系统免疫信号有助于阿片类药物的有害作用，包括痛觉过敏、耐受性、奖励和依赖/戒断。这种作用是由TLR4上的阿片信号介导的，推测是胶质起源。中枢神经系统内皮细胞是否表达TLR4存在争议。如果是这样，它们将很容易被血源性阿片类药物激活，从而促进阿片类药物诱导的促炎反应。这些研究检测了成年原代大鼠中枢神经系统内皮细胞对(-)-吗啡或其莫阿片受体（MOR）无活性代谢物吗啡-3-葡萄糖醛酸盐（M3G）的反应，这两种物质都是已知的TLR4激动剂。我们证明成年大鼠中枢神经系统内皮细胞表达功能性TLR4。M3G激活NFκB，增加肿瘤坏死因子-α (TNFα)和环氧化酶-2 (COX2) mrna，并从这些细胞中释放前列腺素E2。（-）-吗啡诱导的TNFα mRNA和前列腺素E2释放上调被纳美芬预处理所揭示，纳美芬是一种不具有TLR4活性的MOR拮抗剂（与CTAP不同，纳美芬同时具有MOR和TLR4活性），这表明(-)-吗啡在MOR和TLR4共激活之间存在相互作用。为了支持这一观点，mor依赖性蛋白激酶A （PKA）反对TLR4信号，因为PKA抑制（H-89）也揭示了（-）吗啡诱导的TNFα和COX2 mRNA上调。鞘内注射CNS内皮细胞，体外用M3G刺激，产生tlr4依赖性触觉异常性痛。此外，体内皮质弥漫M3G诱导tlr4依赖性血管舒张。最后，内皮细胞TLR4被脂多糖和/或M3G激活被胶质抑制剂AV1013和丙烯茶碱阻断，证明内皮细胞是这类药物的新靶点。这些数据表明(-)-吗啡和M3G可以通过TLR4激活中枢神经系统内皮细胞，引起促炎、生化、形态和行为后遗症。中枢神经系统内皮细胞可能在阿片类药物诱导的效应、被假定的神经胶质抑制剂阻断的现象以及更广泛的tlr4介导的现象中具有意想不到的作用。
CNS immune signaling contributes to deleterious opioid effects including hyperalgesia, tolerance, reward, and dependence/withdrawal. Such effects are mediated by opioid signaling at TLR4, presumptively of glial origin. Whether CNS endothelial cells express TLR4 is controversial. If so, they would be well positioned for activation by blood-borne opioids, contributing to opioid-induced pro-inflammatory responses. These studies examined adult primary rat CNS endothelial cell responses to (-)-morphine or its mu-opioid receptor (MOR) inactive metabolite morphine-3-glucuronide (M3G), both known TLR4 agonists. We demonstrate that adult rat CNS endothelial cells express functional TLR4. M3G activated NFκB, increased tumor necrosis factor-α (TNFα) and cyclooxygenase-2 (COX2) mRNAs, and released prostaglandin E2 from these cells. (-)-Morphine-induced upregulation of TNFα mRNA and prostaglandin E2 release were unmasked by pre-treatment with nalmefene, a MOR antagonist without TLR4 activity (unlike CTAP, shown to have both MOR- and TLR4-activity), suggestive of an interplay between MOR and TLR4 co-activation by (-)-morphine. In support, MOR-dependent Protein Kinase A (PKA) opposed TLR4 signaling, as PKA inhibition (H-89) also unmasked (-)-morphine-induced TNFα and COX2 mRNA upregulation. Intrathecal injection of CNS endothelial cells, stimulated in vitro with M3G, produced TLR4-dependent tactile allodynia. Further, cortical suffusion with M3G in vivo induced TLR4-dependent vasodilation. Finally, endothelial cell TLR4 activation by lipopolysaccharide and/or M3G was blocked by the glial inhibitors AV1013 and propentofylline, demonstrating endothelial cells as a new target of such drugs. These data indicate that (-)-morphine and M3G can activate CNS endothelial cells via TLR4, inducing proinflammatory, biochemical, morphological, and behavioral sequalae. CNS endothelial cells may have previously unanticipated roles in opioid-induced effects, in phenomena blocked by presumptive glial inhibitors, as well as TLR4-mediated phenomena more broadly.
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影响因子：
25
作者：
Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
通讯作者：
De Koninck Y
影响因子：
3.5
作者：
Ai, WD;Gong, JH;Yu, L
通讯作者：
Yu, L
DOI：
10.3758/bf03201438
发表时间：
1986-12-01
期刊：
BEHAVIOR RESEARCH METHODS INSTRUMENTS & COMPUTERS
影响因子：
--
作者：
HARVEY, LO
通讯作者：
HARVEY, LO
影响因子：
9.3
作者：
Due MR;Piekarz AD;Wilson N;Feldman P;Ripsch MS;Chavez S;Yin H;Khanna R;White FA
通讯作者：
White FA
DOI：
10.1523/jneurosci.4595-08.2009
发表时间：
2009-01-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Horvath RJ;DeLeo JA
通讯作者：
DeLeo JA