Endogenous Opioid Dysfunction, Stress, and Risk for Smoking Relapse

摘要 压力是最常见的吸烟复发的诱因之一。它增加了 长期吸烟者吸烟并加速戒烟者向完全复发的进展 吸烟者。这种复发风险在存在其他负面情绪状态时尤其高， 包括焦虑、易怒、抑郁和渴望，尤其是女性。我们之前的研究已经 发现下丘脑-垂体-肾上腺皮质(HPA)轴和内源性阿片类药物改变 吸烟者应激反应的系统(EOS)调节。我们发现吸烟者会表现出 基础HPA活性增强，2)皮质醇对多种急性应激反应减弱 3)减量促肾上腺皮质激素(ACTH)可以预测早期吸烟复发。 以及皮质醇对压力的反应。最近使用阿片类药物阻断挑战的结果表明 吸烟者与非吸烟者相比，阿片类药物对HPA应激反应的钝化调节； 似乎能使阿片类药物对应激反应的调节明显正常化。血管紧张素转换酶的临床意义 改变的阿片类药物对应激反应的调节尚未在临床背景下进行测试 戒烟和复发。在之前发现的基础上，我们计划在这项新研究中采取 通过确定使用阿片类药物的复发风险指数来研究成瘾复发的新方法 HPA应激反应模式。我们的假设是，表现出钝性HPA压力的吸烟者 对阿片类药物阻断的反应更有可能在戒烟尝试的早期复发。钝化阿片类药物 调节有助于低效的应激反应，并可能加剧对渴望和 戒断症状。我们将建立改变的内源性阿片调节之间的联系 HPA戒烟期间的压力反应、戒断症状和渴求。我们将开发一种 使用HPA对压力的反应和HPA对压力的反应预测早期吸烟复发的模型 内源性阿片类药物阻断。最后，我们将考察HPA对压力反应的性别差异， 在HPA对阿片类药物阻断的反应中，在复发的预测指标中。这项研究代表着一步 在翻译已建立的成瘾和压力的临床前神经生物学模型方面取得了进展。它是 以理论为基础，以重要的初步结果为基础，并使用严谨和可重复的 程序。证明阿片类药物挑战在预测复发方面的有效性是一个新的方向 成瘾复发研究将能够索引两条重要的应激生物途径， 为烟草成瘾的长期影响提供了一种新的机制和治疗的标志 结果和复发概率。这将有助于未来针对易受影响的人进行的努力 新的或现有的行为和药物治疗对他们复发风险的压力。 降低复发率将减少烟草的使用及其对健康的破坏性影响。

Summary Stress is one of the most commonly reported triggers of smoking relapse. It increases frequency of smoking among chronic smokers and accelerates progression towards full relapse among abstinent smokers. This relapse risk is particularly high in the presence of other negative affective states, including anxiety, irritability, depression, and craving, especially in women. Our previous research has demonstrated altered hypothalamic-pituitary-adrenocortical (HPA) axis and endogenous opioid system (EOS) regulation of the stress response in smokers. We found that 1) smokers exhibit enhanced basal HPA activity, 2) they exhibit decreased cortisol responses to multiple acute stress procedures, and 3) early smoking relapse can be predicted by attenuated adrenocorticotropin (ACTH) and cortisol responses to stress. Recent results using an opioid blockade challenge demonstrate blunted opioid regulation of the HPA stress response in smokers relative to nonsmokers; and smoking appears to acutely normalize opioid regulation of the stress response. The clinical significance of altered opioid regulation of the stress response has not been tested in the clinical context of smoking cessation and relapse. Building on previous findings, we plan in this new study to take a novel approach in addiction relapse research by identifying indices of risk for relapse using opioid- HPA stress response patterns. Our hypothesis is that smokers who exhibit blunted HPA stress response to opioid blockade are more likely to relapse early in their cessation attempt. Blunted opioid regulation contributes to inefficient stress response and may exacerbate stress effects on craving and withdrawal symptoms. We will establish the link between altered endogenous opioid regulation of the HPA stress response, withdrawal symptoms, and craving during smoking cessation. We will develop a model to predict early smoking relapse using HPA responses to stress and HPA responses to endogenous opioid blockade. Finally, we will examine sex differences in the HPA response to stress, in the HPA response to opioid blockade, and in predictors of relapse. This research represents a step forward in translating established preclinical neurobiological models of addiction and stress. It is grounded in theory, builds on important preliminary results, and uses rigorous and reproducible procedures. Demonstrating the utility of an opioid challenge in predicting relapse is a novel direction in addiction relapse research that will enable indexing two important stress biological pathways, providing both a novel mechanism of long-term effects of tobacco addiction and a marker of treatment outcome and relapse probability. This will facilitate future efforts targeting those susceptible to effects of stress on their risk for relapse with new or existing behavioral and pharmacological treatments. Reducing relapse rates will reduce tobacco use and its devastating health effects.