OPIATE WITHDRAWAL-INDUCED NEGATIVE REINFORCEMENT AND DESCENDING FACILITATION

阿片类药物提供的正强化被认为是促进药物依赖的主要因素。 滥用和依赖。然而，阿片类药物也会产生一系列“负面”影响， 在阿片剂给药期间，尤其是在戒断期间表达。阿片类药物戒断 是令人不快的，并可能提供负强化并导致药物依赖。因此， 积极和消极的强化可能会导致阿片类药物的强迫使用，这是一个关键特征， “鸦片成瘾”。阿片类药物产生负面影响的机制尚不清楚。我们 初步数据表明，阻断延髓头端腹内侧（RVM）下行易化， 阻止阿片戒断的躯体和自主体征的表达，表明易化性流出 在介导伤害感受（即，阿片诱导的痛觉过敏）和许多非伤害性 戒断综合征的特征。我们假设阿片诱导的下行易化 从RVM和随后的脊髓强啡肽的上调是必不可少的许多表达， 包括鸦片类药物戒断的阴性症状。表达的机制 因此，戒断综合征的机制也可能促进负强化， 可能导致阿片类药物依赖、持续使用和滥用阿片类药物以及药物寻求行为。 这个假设将探讨与四个具体的目的：首先，我们将表征原伤害感受 RVM中的递质，其中可以介导纳洛酮催促戒断。第二，我们将确定 阻止RVM下行易化是否能阻止阿片诱导的身体依赖 （纳洛酮诱导或自发戒断）。第三，我们将确定是否封锁 脊髓强啡肽或缓激肽B2受体的前伤害性作用将阻止戒断。四是 将决定是否阻断下行易化阻断撤回引起的厌恶/负强化。 这些研究评估了可能导致负强化、药物 依赖和滥用。

The positive reinforcement provided by opiates have been considered as primary factors in promoting drug abuse and dependence. However, opiates also produce a host of "negative" effects which can manifest both during opiate administration and which are particularly expressed during withdrawal. Withdrawal from opiates is unpleasant and may provide negative reinforcement and contribute to drug dependence. Thus, both positive and negative reinforcement are likely to contribute to the compulsive use of opioids, a critical feature of "opioid addiction". The mechanisms by which opiates produce negative effects are unknown. Our preliminary data indicate that blockade of descending facilitation in the rostral ventromedial medulla (RVM) prevents expression of somatic and autonomic signs of opiate withdrawal indicating that facilitatory outflow from the RVM is critical in mediating both nociceptive (i.e., opiate-induced hyperalgesia) and many nonnociceptive features of the withdrawal syndrome. We hypothesize that opiate-induced descending facilitation from the RVM and subsequent upregulation of spinal dynorphin are essential for the expression of many of the negative symptoms which comprise withdrawal from opiates. Mechanisms which underlie the expression of the withdrawal syndrome thus also represent mechanisms likely promote negative reinforcement which may contribute to opiate dependence, the continued use and abuse of opiates and drug seeking behavior. This hypothesis will be explored with four Specific Aims: First, we will characterize pronociceptive transmitters in the RVM in which can mediate naloxone-precipitated withdrawal. Second, we will determine whether prevention of descending facilitation from the RVM prevents opiate-induced physical dependence (naloxone-induced or spontaneous withdrawal). Third, we will determine whether blockade of the pronociceptive actions of spinal dynorphin, or the bradykinin B2 receptor will prevent withdrawal. Fourth, we will determine if blockade of descending facilitation blocks withdrawal-induced aversion/negative reinforcement. These studies assess mechanisms which may contribute to negative reinforcement, drug dependence and abuse.