Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, USA.
Medical Scientist Training Program, University of Virginia, Charlottesville, Virginia, USA.
Neuroendocrinology. 2023;113(11):1099-1111. doi: 10.1159/000529997. Epub 2023 Mar 6.
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. Thus, the goal of this study was to determine the impact of estradiol on vulnerability in females in a rat model of OUD.
Following self-administration training, ovariectomized (OVX) females with (E) or without (V) estradiol replacement were given extended (24 h/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.
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.
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.
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影响；物质使用障碍中性别差异的一个主要理论是，这些差异归因于雌激素增强了女性的脆弱性。然而，大多数证据都是针对精神兴奋剂和酒精的；而关于阿片类药物的证据则很少。因此，本研究的目的是确定在 OUD 的大鼠模型中，雌激素对女性易感性的影响。
在自我给药训练后，给予去卵巢（OVX）雌性大鼠（E）或不给予（V）雌激素替代物，进行延长（每天 24 小时）、间歇性（每小时 2 到 5 分钟试验）的芬太尼暴露 10 天。然后，评估 OUD 的三个关键特征的发展，包括身体依赖，通过戒断期间体重减轻的幅度和时间过程来定义；使用递增比例时间表评估对芬太尼的增强动机；以及通过戒断/线索诱导复发性评估复发易感性。在戒断 14 天后，当表型已知高度表达时，检查了后两个特征。
OVX+E 雌性大鼠在延长的、间歇性的条件下自我给药的芬太尼水平明显更高，并表现出更长的身体依赖时间过程，对芬太尼的动机增加更大，对芬太尼相关线索的再激发作用的敏感性增强，与 OVX+V 大鼠相比。在戒断期间，OVX+E 但不是 OVX+V 雌性大鼠也观察到严重的健康并发症。
这些结果表明，与精神兴奋剂和酒精的发现一样，雌激素增强了女性对发展类阿片类药物成瘾特征和严重阿片类药物相关健康并发症的易感性。
