The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice.
The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice.
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Sigma-2受体 /跨膜蛋白97（σ2R / TMEM97）调节剂JVW-1034可减少雄性小鼠的大量饮酒和相关疼痛状态。
DOI：
10.1016/j.neuropharm.2020.108409
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发表时间：
2021-02-15
影响因子：
4.7
通讯作者：
Sabino V
中科院分区：
文献类型：
--
作者：
Quadir SG;Tanino SM;Rohl CD;Sahn JJ;Yao EJ;Cruz LDR;Cottone P;Martin SF;Sabino V
酒精使用障碍（AUD）是一种慢性复发性疾病，其特征是强迫性酒精摄入，对酒精摄入失去控制，以及在阻止饮酒时的负面情绪状态。AUD也与疼痛密切相关，因为反复饮酒会导致戒断期间疼痛敏感性增加。σ-2受体（σ 2 R/TMEM 97）是一种重要的跨膜蛋白，参与胆固醇稳态和脂质代谢。选择性σ 2 R/Tmem 97调节剂最近已显示在神经性疼痛的动物模型中减轻机械超敏性以及在C. elegans和减少大鼠饮酒，表明这种蛋白质在酒精相关行为中的潜在关键作用。在这项研究中，我们测试了一种有效的和选择性的σ 2 R/TMEM 97配体，JVW-1034，对重度饮酒和酒精诱导的疼痛状态的影响，使用间歇性访问模型的小鼠。施用JVW-1034降低了乙醇摄入量和对乙醇的偏好，而不影响水摄入量、总流体摄入量或食物摄入量。值得注意的是，这种效果是酒精特有的，因为JVW-1034对蔗糖摄入没有影响。此外，JVW-1034降低了乙醇戒断小鼠的热痛觉过敏和机械超敏反应。我们的数据提供了重要的证据，即用小分子调节σ 2 R/TMEM 97可以介导重度饮酒以及慢性酒精诱导的疼痛敏感性增加，从而确定了AUD和相关疼痛状态的有希望的新药理学靶点。
Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol intake, loss of control over alcohol intake, and a negative emotional state when access to alcohol is prevented. AUD is also closely tied to pain, as repeated alcohol drinking leads to increased pain sensitivity during withdrawal. The sigma-2 receptor, recently identified as transmembrane protein 97 (σ2R/TMEM97), is an integral membrane protein involved in cholesterol homeostasis and lipid metabolism. Selective σ2R/Tmem97 modulators have been recently shown to relieve mechanical hypersensitivity in animal models of neuropathic pain as well as to attenuate alcohol withdrawal signs in C. elegans and to reduce alcohol drinking in rats, suggesting a potential key role for this protein in alcohol-related behaviors. In this study, we tested the effects of a potent and selective σ2R/TMEM97 ligand, JVW-1034, on heavy alcohol drinking and alcohol-induced heightened pain states in mice using an intermittent access model. Administration of JVW-1034 decreased both ethanol intake and preference for ethanol, without affecting water intake, total fluid intake, or food intake. Notably, this effect was specific for alcohol, as JVW-1034 had no effect on sucrose intake. Furthermore, JVW-1034 reduced both thermal hyperalgesia and mechanical hypersensitivity in ethanol withdrawn mice. Our data provide important evidence that modulation of σ2R/TMEM97 with small molecules can mediate heavy alcohol drinking as well as chronic alcohol-induced heightened pain sensitivity, thereby identifying a promising novel pharmacological target for AUD and associated pain states.
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影响因子：
7.6
作者：
Dore, Riccardo;Iemolo, Attilio;Sabino, Valentina
通讯作者：
Sabino, Valentina
影响因子：
3.2
作者：
Arout, Caroline A.;Perrino, Albert C.;Petrakis, Ismene L.
通讯作者：
Petrakis, Ismene L.
DOI：
10.1523/jneurosci.4991-12.2013
发表时间：
2013-05-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Btesh J;Fischer MJM;Stott K;McNaughton PA
通讯作者：
McNaughton PA
影响因子：
10.6
作者：
Garces-Ramirez, Linda;Green, Jennifer L.;Hiranita, Takato;Kopajtic, Theresa A.;Mereu, Maddalena;Thomas, Alexandra M.;Mesangeau, Christophe;Narayanan, Sanju;McCurdy, Christopher R.;Katz, Jonathan L.;Tanda, Gianluigi
通讯作者：
Tanda, Gianluigi
影响因子：
11
作者：
Bloodgood DW;Hardaway JA;Stanhope CM;Pati D;Pina MM;Neira S;Desai S;Boyt KM;Palmiter RD;Kash TL
通讯作者：
Kash TL