OPIATE WITHDRAWAL-INDUCED NEGATIVE REINFORCEMENT AND DESCENDING FACILITATION

阿片戒断引起的负强化和下降便利

• 批准号: 8025977
• 负责人: Frank Porreca
• 金额: $ 24.64万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025977
• 关键词: Acute; Affect; Affective Symptoms; Agonist; Animals; Anxiety; BDKRB2 gene; Body Weight decreased; Bradykinin B2 Receptor; Bradykinin Receptor; Canis familiaris; Data; Dependence; Development; Diarrhea; Drug Addiction; Drug abuse; Drug usage; Dynorphins; Exposure to; Glutamates; Human; Hyperalgesia; Immune Sera; Infusion procedures; Knockout Mice; Laboratory Animals; Lead; Lesion; Mediating; Morphine; Motor; NR2A NMDA receptor; Naloxone; Nature; Negative Reinforcements; Nociception; Opiate Addiction; Opiates; Opioid; Pain; Peptides; Physical Dependence; Positive Reinforcements; Prevention; Probability; Production; Rattus; Rodent; Role; Saline; Secondary to; Sensory Thresholds; Slice; Societies; Spinal; Spinal Anesthesia; Spinal Cord; Substance P; Substance Withdrawal Syndrome; Symptoms; System; Testing; Time; Tooth structure; Up-Regulation; Withdrawal; delta opioid receptor; design; drug seeking behavior; dysphoria; effective therapy; experience; inhibitor/antagonist; non-opioid analgesic; opioid abuse; osmotic minipump; preclinical study; prevent; prodynorphin; programs; receptor; response; sensory stimulus; subcutaneous

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.

阿片类药物提供的正强化被认为是促进药物作用的主要因素。 虐待和依赖。然而，阿片类药物也会产生一系列“负面”影响，这可以表现为： 在阿片类药物给药期间，特别是在戒断期间表现出来。戒断阿片类药物 是令人不愉快的，可能会提供负面强化并导致药物依赖。因此，两者 积极和消极的强化可能会导致强迫性使用阿片类药物，这是一个关键特征 的“阿片类药物成瘾”。阿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，延髓头端腹内侧 (RVM) 的下降易化受阻 防止阿片戒断的躯体和自主神经信号的表达，表明易化流出 来自 RVM 的信号对于介导伤害性感受（即阿片类药物引起的痛觉过敏）和许多非伤害性感受至关重要 戒断综合症的特征。我们假设阿片类药物引起的下降促进 来自 RVM 和随后脊髓强啡肽的上调对于许多表达至关重要 包括阿片类药物戒断在内的阴性症状。该表达背后的机制 因此，戒断综合症的机制也代表了可能促进负强化的机制， 可能会导致阿片类药物依赖、持续使用和滥用阿片类药物以及寻求毒品的行为。 该假设将通过四个具体目标进行探讨：首先，我们将描述伤害感受的特征 RVM 中的递质可以介导纳洛酮沉淀的戒断反应。其次，我们将确定 预防 RVM 的下降促进是否可以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 受体的促伤害感受作用会阻止戒断。第四，我们 将确定对下降促进的封锁是否会阻止撤回引起的厌恶/负强化。 这些研究评估了可能有助于负强化、药物 依赖和虐待。