Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice.
Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice.
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DOI：
10.1016/j.drugalcdep.2016.08.017
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发表时间：
2016-10-01
影响因子：
4.2
通讯作者：
van Rijn RM
中科院分区：
文献类型：
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作者：
Alongkronrusmee D;Chiang T;van Rijn RM
作为一种合法药物，酒精经常被滥用，据估计，美国有1700万成年人患有酒精使用障碍。重度酗酒者可能会出现戒断症状，包括焦虑和机械异常性疼痛，这些症状会促进复发。这种现象背后的分子机制尚不清楚，这阻碍了新疗法的发展。在这里，我们研究delta阿片受体（DORs）是否在酒精戒断诱导的机械性异常痛（AWiMA）中发挥积极作用，以及DOR激动剂是否可以缓解AWiMA的镇痛作用。为了研究AWiMA，我们建立并验证了成年雄性野生型和DOR敲除C57BL/6小鼠通过自愿饮酒模型或灌胃暴露模型暴露于酒精。我们还使用dor选择性激动剂TAN-67和拮抗剂纳曲多来检查DORs在AWiMA中的作用，使用von Frey机械异常性疼痛模型测量。我们用3 g/kg酒精灌胃小鼠3周，建立了酒精戒断性焦虑和机械异常性疼痛模型。与对照组小鼠相比，DOR敲除小鼠以及DORs药物阻断小鼠的AWiMA加重和延长。然而，在酒精灌胃小鼠戒断期间，坦-67引起的镇痛作用减弱。DORs似乎在建立AWiMA中起着保护作用。我们目前的结果表明，DORs可以有针对性地预防或减少酒精使用期间AWiMA的发展；然而，在主动戒断期间，DORs可能不是治疗AWiMA的合适靶点。
As a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA. To study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia. We created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3 g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice. DORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal.