Cannabinoid modulation of neurotransmission during morphine tolerance

描述（由申请人提供）：吗啡等阿片类药物是用于治疗疼痛的最重要工具之一，但由于耐受性和其他负面副作用的发展，其使用受到限制。大麻素，如9-四氢大麻酚（THC）也用于缓解疼痛，然而它们的低功效和副作用也限制了它们的临床用途。阿片类药物和大麻素以多种方式相互作用，比单独使用任何一种药物都能更好地缓解疼痛。最近的人类临床数据表明，大麻素给药可以改善已经服用阿片类药物治疗慢性疼痛的患者的疼痛缓解。我们的初步数据支持这些发现，并表明，这种影响至少部分介导的中脑导水管周围灰质（PAG）。PAG主要参与下行疼痛调节和吗啡耐受的发展。拟议研究的目标是阐明阿片类药物耐受性产生后，PAG中发生的大麻素信号传导和神经传递的细胞适应。以下两个具体目标将使用体外电生理学技术来解决这些目标：1）表征慢性吗啡暴露后大麻素介导的突触传递的变化。2)确定吗啡耐受诱导的PAG中大麻素调节神经传递变化的细胞机制。目标1和2中的实验将采用全细胞膜片钳技术来测量慢性阿片类药物暴露后突触传递的变化，并确定这些变化背后的分子机制。还将采用大鼠行为测试来评估抗伤害感受，并验证吗啡耐受性的发展。拟议的研究将确定慢性阿片类药物治疗后发生变化的分子机制，这些变化发生在与阿片类药物耐受性密切相关的大脑区域。阿片类药物/大麻素相互作用的领域仍在发展中，表征该系统的生理学将对该领域产生重大影响。充分了解这种相互作用对于我们确定大麻素相关细胞靶点的长期目标至关重要，这些靶点可用于克服耐受性和改善阿片类药物的镇痛效果。这种创新可能会导致临床疼痛管理的重大进展。

DESCRIPTION (provided by applicant): Opioids such as morphine are among the most important tools used to treat pain, however their use is limited due to the development of tolerance and other negative side effects. Cannabinoids such as ¿9- tetrahydracannabinol (THC) are also used for pain relief, however their low efficacy and side effects also limit their clinical utility. Opioids and cannabinoids interact in several ways to produce better pain relief than either drug alone. Recent clinical data in humans demonstrates that cannabinoid administration can improve pain relief in patients already taking opioids for chronic pain. Our preliminary data supports these findings, and suggests that this effect is at least partially mediated by the midbrain periaqueductal gray (PAG). The PAG is critically involved in descending pain modulation and the development of morphine tolerance. The goal of the proposed studies is to elucidate the cellular adaptations in cannabinoid signaling and neurotransmission that occur in the PAG after the development of opioid tolerance. The following two Specific Aims will address these goals, using in vitro electrophysiology techniques: 1) Characterize the changes in cannabinoid-mediated synaptic transmission after chronic morphine exposure. 2) Determine the cellular mechanisms underlying morphine tolerance-induced changes in cannabinoid modulation of neurotransmission in the PAG. The experiments in Aims 1 and 2 will employ whole-cell patch clamp techniques to measure changes in synaptic transmission after chronic opioid exposure, and to determine the molecular mechanisms underlying these changes. Behavioural testing in rats will also be employed to assess antinociception, and verify the development of morphine tolerance. The proposed studies will identify the molecular mechanisms underlying the changes that occur following chronic opioid treatment, in a brain region that is critically involved in opioid tolerance. The field of opioid/cannabinoid interaction is still developing, and characterizing the physiology of this system will have a significant impact on the field. Full understanding of this interaction is critial to our long-term goal of identifying cannabinoid-related cellular targets that may be used to overcome tolerance and improve the analgesic efficacy of opioids. Such an innovation could lead to a major advance in clinical pain management.