Cannabinoid modulation of neurotransmission during morphine tolerance

项目总结： 阿片类药物，如吗啡，是治疗疼痛的最重要工具之一，然而它们的使用 有限，由于发展耐受性和其他负面副作用。大麻类物质，如�9- 四氢大麻酚(THC)也可用于止痛，但其疗效低，副作用大。 限制了它们的临床应用。阿片类药物和大麻类物质以多种方式相互作用，产生更好的止痛效果 而不是单独服用任何一种药物。我们的初步数据显示，大麻素的抗伤害作用在 对吗啡耐受的动物，这种影响至少部分由中脑介导 导水管周围灰质(PAG)。PAG在下行痛觉调制中起重要作用 吗啡耐受性的发展。这项拟议研究的目标是阐明细胞 在阿片类药物耐受性形成后，PAG中发生的适应，并决定如何 这些适应影响大麻素介导的抗伤害感受和神经传递。这个 使用体外电生理学技术，以下两个具体目标将解决这些目标：1) 确定吗啡耐受诱导大麻素增强的细胞机制 PAG中的止痛作用；2) �S内源性大麻素系统在术后适应特性的研究 慢性阿片类药物暴露。AIMS 1和AIMS 2的实验将使用全细胞膜片钳技术 测量慢性阿片类药物暴露后突触传递的变化，并确定分子 这些变化背后的机制。老鼠的行为测试也将被用来评估 大麻素的抗伤害作用，并验证吗啡耐受性的发展。建议进行的研究 将确定慢性阿片类药物后发生变化的分子机制 治疗，在大脑中与阿片类药物耐受密切相关的区域。阿片/大麻类药物领域 交互仍处于初级阶段，表征这一系统的生理学将具有重要意义 对赛场的影响。对这种相互作用的充分理解对于我们确定 大麻素相关细胞靶点可用于克服耐受性和改善 阿片类药物的止痛效果。这样的创新可能会导致临床疼痛的重大进步 管理层。

PROJECT SUMMARY: 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. Our preliminary data demonstrate that cannabinoid antinociception is enhanced in morphine-tolerant animals, and 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 goals of the proposed studies are to elucidate the cellular adaptations that occur in the PAG after the development of opioid tolerance, and determine how these adaptations affect cannabinoid-mediated antinociception and neurotransmission. The following two Specific Aims will address these goals, using in vitro electrophysiology techniques: 1) Determine the cellular mechanisms underlying morphine tolerance-induced enhancement of cannabinoid analgesia in the PAG, and 2) Characterize adaptations in the PAG�s endocannabinoid system after chronic opioid exposure. 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 cannabinoid 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 in its infancy, and characterizing the physiology of this system will have a significant impact on the field. Full understanding of this interaction is critical 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.