CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward.
CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward.
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DOI：
10.1016/j.bbi.2017.11.006
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Paris JJ
中科院分区：
文献类型：
--
作者：
Gonek M;McLane VD;Stevens DL;Lippold K;Akbarali HI;Knapp PE;Dewey WL;Hauser KF;Paris JJ
HIV-1调节蛋白，转录的反式激活因子（达特），与阿片类药物相互作用，以增强CNS内的神经炎症和神经变性。这些作用可能涉及C-C趋化因子受体5型（CCR 5）;然而，CCR 5对达特/阿片类药物相互作用的行为贡献尚不清楚。使用一个转基因小鼠模型，表达HIV-1达特蛋白在GFAP调节，强力霉素诱导的方式，我们评估吗啡耐受性，依赖性和奖励。为了评估CCR 5对这些作用的影响，在吗啡给药前，用口服载体或CCR 5拮抗剂马拉韦罗预处理小鼠。我们发现HIV-1达特表达显著减弱了急性吗啡（2 - 64 mg/kg，i. p.）非耐受性小鼠。与此一致，达特减轻了吗啡耐受小鼠的戒断症状。马拉韦罗预处理阻断了达特的作用，恢复了非耐受小鼠的吗啡效力，并恢复了吗啡耐受小鼠的戒断行为。吗啡给药后24小时，HIV-1达特显著增强（103.5倍）吗啡条件性位置偏爱，马拉韦罗进一步增强这些作用（105.7倍）。马拉韦罗本身没有产生可测量的行为影响。蛋白质阵列分析显示，只有轻微的变化，细胞因子的配置文件时，吗啡急性或反复给药;然而，24小时后，吗啡给药，几种细胞因子的表达大大增加，包括内源性CCR 5趋化因子配体（CCL 3，CCL 4和CCL 5），以及CCL 2。达特进一步升高了几种细胞因子的水平，而马拉韦罗预处理减弱了这些作用。这些数据表明，CCR 5介导HIV-1 Tat诱导的阿片类药物的抗伤害性效力和奖励特性改变的关键方面。
The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP-regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration. We found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine (2 – 64 mg/kg, i.p.) in non-tolerant mice. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Twenty-four hours following morphine administration, HIV-1 Tat significantly potentiated (∼3.5-fold) morphine-conditioned place preference and maraviroc further potentiated these effects (∼5.7-fold). Maraviroc exerted no measurable behavioral effects on its own. Protein array analyses revealed only minor changes to cytokine profiles when morphine was administered acutely or repeatedly; however, 24 h post morphine administration, the expression of several cytokines was greatly increased, including endogenous CCR5 chemokine ligands (CCL3, CCL4, and CCL5), as well as CCL2. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. These data demonstrate that CCR5 mediates key aspects of HIV-1 Tat-induced alterations in the antinociceptive potency and rewarding properties of opioids.
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影响因子：
6.2
作者：
El-Hage, Nazira;Bruce-Keller, Annadora J.;Knapp, Pamela E.;Hauser, Kurt F.
通讯作者：
Hauser, Kurt F.
DOI：
10.1186/cc5055
发表时间：
2006
期刊：
Critical care (London, England)
影响因子：
--
作者：
Cavaillon JM;Adib-Conquy M
通讯作者：
Adib-Conquy M
DOI：
10.1097/qad.0b013e3283639804
发表时间：
2013-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
El-Hage N;Dever SM;Podhaizer EM;Arnatt CK;Zhang Y;Hauser KF
通讯作者：
Hauser KF
影响因子：
4.9
作者：
Angelakis, Emmanouil;Million, Matthieu;Raoult, Didier
通讯作者：
Raoult, Didier
影响因子：
7.3
作者：
Akguen, Eyup;Javed, Muhammad I.;Lunzer, Mary M.;Powers, Michael D.;Sham, Yuk Y.;Watanabe, Yoshikazu;Portoghese, Philip S.
通讯作者：
Portoghese, Philip S.