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Cannabinoid modulation of neurotransmission during morphine tolerance

吗啡耐受过程中大麻素对神经传递的调节

基本信息

批准号：
8907086
负责人：
Adrianne Rae Wilson-Poe
金额：
$ 5.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8907086
关键词：
Absence of pain sensation Address Adverse effects Affect Agonist Analgesics Animals Behavioral Brain Brain region CNR1 gene Cannabinoids Cells Chronic Clinical Data Development Disinhibition Drug usage Effectiveness Electrophysiology (science)Endocannabinoids Exposure to Goals In Vitro Knowledge Laboratories Lead Life Measures Medial Mediating Midbrain structure Molecular Morphine Neurotransmitters Opioid Outcomes Research Pain Pain management Patch-Clamp Techniques Pathway interactions Pharmaceutical Preparations Physiology Play Process Property Quality of life Rattus Role Spinal cord posterior horn Synaptic Transmission System Techniques Testing Tetrahydrocannabinol Therapeutic base behavior test cannabinoid receptor cellular targeting clinically relevant gamma-Aminobutyric Acid improved infancy inhibitor/antagonist innovation midbrain central gray substance neurotransmission presynaptic research study tool

项目摘要

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.

项目概要：吗啡等阿片类药物是用于治疗疼痛的最重要工具之一，但它们的用途是由于耐受性和其他负面副作用的发展而受到限制。大麻素，例如 �9- 四氢大麻酚 (THC) 也用于缓解疼痛，但其功效低且副作用也很大限制了它们的临床效用。阿片类药物和大麻素以多种方式相互作用，可以更好地缓解疼痛比单独使用任何一种药物。我们的初步数据表明，大麻素的镇痛作用在吗啡耐受的动物，并且这种效应至少部分是由中脑介导的导水管周围灰质（PAG）。 PAG 关键参与下行疼痛调节和吗啡耐受性的发展。拟议研究的目标是阐明细胞出现阿片类药物耐受性后 PAG 中发生的适应，并确定如何这些适应影响大麻素介导的镇痛和神经传递。这以下两个具体目标将使用体外电生理学技术来实现这些目标：1) 确定吗啡耐受诱导大麻素增强的细胞机制 PAG 中的镇痛，2) 描述 PAG 内源性大麻素系统的适应特征慢性阿片类药物暴露。目标 1 和 2 中的实验将采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。大鼠行为测试也将用于评估大麻素镇痛，并验证吗啡耐受的发展。拟议的研究将确定慢性阿片类药物发生变化的分子机制在与阿片类药物耐受性密切相关的大脑区域进行治疗。阿片类/大麻素领域相互作用仍处于起步阶段，表征该系统的生理学将具有重要意义对场上的影响。充分理解这种相互作用对于我们识别的长期目标至关重要大麻素相关的细胞靶标可用于克服耐受性并改善阿片类药物的镇痛功效。这样的创新可能会导致临床疼痛的重大进步管理。