OPIATE WITHDRAWAL-INDUCED NEGATIVE REINFORCEMENT AND DESCENDING FACILITATION

阿片类药物所提供的正性强化被认为是促进药物的主要因素 虐待和依赖。然而，鸦片类药物也会产生大量的“负面”影响，这两种影响都可以表现出来。 在阿片类药物使用期间，尤其是在戒断过程中表达。戒断鸦片类药物 是令人不快的，可能会带来负面强化，并导致药物依赖。因此，两者 积极和消极的强化很可能促成阿片类药物的强制使用，这是一个关键特征 “阿片成瘾”。鸦片类药物产生负面影响的机制尚不清楚。我们的 初步数据表明，阻断延髓吻侧腹内侧区(RVM)的下行促进作用 阻止阿片类药物戒断的躯体和自主神经迹象的表达，表明易化性流出 RVM在介导伤害性(即阿片剂诱导的痛敏)和许多非伤害性痛觉过敏中起着关键作用。 戒断综合征的特点。我们假设阿片类药物诱导的下行易化 从RVM和随后的脊髓强啡肽的上调对许多 包括停用鸦片类药物在内的阴性症状。表达方式背后的机制 因此，戒断综合症也代表了可能促进负面强化的机制 可能导致鸦片类药物依赖、阿片类药物的持续使用和滥用以及寻求毒品的行为。 这一假说将以四个具体目标来探讨：第一，我们将描述前伤害性感觉 RVM中可介导纳洛酮催促戒断的递质。第二，我们将确定 预防右室下移易化是否能预防阿片类药物引起的身体依赖 (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受体的致痛作用将防止戒断。第四，我们 将确定阻断下行促进是否阻止戒断诱导的厌恶/负强化。 这些研究评估了可能导致负强化的机制，药物 依赖和虐待。

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.