Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast).
Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast).
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DOI：
10.1016/j.bbi.2008.09.012
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发表时间：
2009-02
影响因子：
15.1
通讯作者：
Johnson, Kirk W.
中科院分区：
文献类型：
--
作者：
Hutchinson, Mark R.;Lewis, Susannah S.;Coats, Benjamen D.;Skyba, David A.;Crysdale, Nicole Y.;Berkelhammer, Debra L.;Brzeski, Anita;Northcutt, Alexis;Vietz, Christine M.;Judd, Charles M.;Maier, Steven F.;Watkins, Linda R.;Johnson, Kirk W.
已有文献证明，吗啡诱导的神经胶质促炎反应有助于阿片类药物镇痛的耐受。在这里，我们检查了以前显示的抑制神经胶质前炎症反应的药物是否可以改变其他临床相关的阿片类药物效应，即戒断或急性止痛。AV411(异丁司特)和米诺环素，具有不同的作用机制，导致神经胶质促炎反应减弱，各自减少纳洛酮沉淀的戒断。对与阿片类药物戒断相关的脑核的分析表明，吗啡改变了神经胶质激活标志物、细胞因子、趋化因子和神经营养因子的表达。AV411可减弱其中许多吗啡诱导的效应。AV411还可以防止在12天的时间内记录的自发戒断引起的多动和体重减轻。值得注意的是，在自发戒断研究中，AV411的治疗相对于吗啡方案的开始被推迟，以便也测试AV411在面对已确定的吗啡依赖时是否仍然有效，事实的确如此。AV411并不是简单地减弱所有阿片类药物的效应，因为AV411与吗啡或羟考酮联合应用可使急性镇痛效力增加3-5倍，这一点从止痛剂剂量反应曲线的左移中可以看出。时程分析显示，AV411对血浆吗啡水平无明显影响，提示增强镇痛作用不是单纯由于吗啡暴露时间延长或血浆浓度升高所致。这些数据支持并扩展了米诺环素对急性阿片类止痛的类似增强作用，再次提供了神经胶质参与的证据。因此，抑制胶质细胞的促炎反应可以显著减少阿片类药物的戒断，同时改善止痛。
Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused 3-to-5-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, whilst improving analgesia.
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影响因子：
3.6
作者：
Dame, JB;Christensen, RD;Juul, SE
通讯作者：
Juul, SE
影响因子：
3.3
作者：
DOUGHERTY, PM;PELLIS, NR;DAFNY, N
通讯作者：
DAFNY, N
影响因子：
3.3
作者：
Huitinga, I;van der Cammen, M;Swaab, D
通讯作者：
Swaab, D
影响因子：
2.5
作者：
Alonso, Elba;Garrido, Elisa;Alguacil, Luis F.
通讯作者：
Alguacil, Luis F.
影响因子：
3
作者：
Azar, MR;Ahmed, SH;Koob, GF
通讯作者：
Koob, GF