Rationale: Women are more vulnerable than men in many aspects of opioid use disorder (OUD); a major theory of sex differences in substance use disorders is that these differences are due to ovarian hormones with estradiol enhancing vulnerability in females. However, most of this evidence is for psychostimulants and alcohol; evidence with opioids is sparse. Objective: The goal of this study was to determine the impact of estradiol on vulnerability in females in a rat model of OUD. Method: Following self-administration training, ovariectomized (OVX) females with (E) or without (V) estradiol replacement were given extended (24h/day), intermittent-access (2, 5 min trials/h) to fentanyl for 10 days. Then, the development of three key features of OUD were assessed, including physical dependence, defined by the magnitude and time-course of weight loss during withdrawal, an enhanced motivation for fentanyl, assessed using a progressive-ratio schedule, and relapse vulnerability, assessed using an extinction/cue-induced reinstatement procedure. These later two characteristics were examined following 14 days of withdrawal when the phenotypes are known to be highly expressed. Results: OVX+E females self-administered markedly higher levels of fentanyl under extended, intermittent-access conditions and showed a longer time-course of physical dependence, a greater increase in motivation for fentanyl, and an enhanced sensitivity to the reinstating effects of fentanyl-associated cues compared to OVX+V rats. Severe health complications were also observed in OVX+E, but not OVX+V females, during withdrawal. Conclusion: These results indicate that, as with findings with psychostimulants and alcohol, estradiol enhances vulnerability in females to developing opioid addiction-like features and serious opioid-related health complications.


中文翻译：

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雌二醇促进阿片类药物使用障碍雌性大鼠模型中类似加法特征的发展

理由：在阿片类药物使用障碍 (OUD) 的许多方面，女性比男性更容易受到伤害；关于物质使用障碍中性别差异的一个主要理论是，这些差异是由于卵巢激素和雌二醇增加了女性的脆弱性。然而，大部分证据都是针对精神兴奋剂和酒精的。阿片类药物的证据很少。目的：本研究的目的是确定雌二醇对 OUD 大鼠模型中雌性脆弱性的影响。方法：在自我给药培训后，接受 (E) 或不接受 (V) 雌二醇替代的卵巢切除 (OVX) 女性接受延长（24 小时/天）、间歇性（2、5 分钟试验/小时）芬太尼治疗 10 天。然后，对 OUD 的三个关键特征的发展进行了评估，包括身体依赖性（由戒断期间体重减轻的幅度和时间过程定义）、使用渐进比例时间表评估的芬太尼增强动机以及评估的复发脆弱性。使用灭绝/提示诱导的恢复程序。停药 14 天后，对后两个特征进行了检查，此时已知表型高度表达。结果：OVX+E 女性在延长、间歇性使用条件下自行施用的芬太尼水平明显较高，并表现出较长的身体依赖性时间过程、芬太尼动机的更大增加以及对芬太尼恢复作用的敏感性增强-与 OVX+V 大鼠相比相关线索。在戒断期间，OVX+E 女性（而非 OVX+V 女性）也观察到严重的健康并发症。结论：这些结果表明，与精神兴奋剂和酒精的研究结果一样，雌二醇会增加女性出现阿片类药物成瘾样特征和严重的阿片类药物相关健康并发症的可能性。