CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence

尽管存在显著的局限性，阿片类药物仍然是治疗严重急性和慢性疼痛的主要药物。 伴随阿片类药物的长期治疗使用的两个临床上显著的局限性是：（1） 耐受性的发展（需要递增剂量的阿片样物质以维持期望的治疗益处，或 导致恒定剂量的益处减少）和（2）身体依赖性（戒断症状， 停止阿片类药物的使用，这是非常不愉快的，并寻求避免可能会增加风险， 阿片类药物成瘾）。目前，还没有降低阿片类药物耐受性或抑制阿片类药物耐受性的实用方法。 身体依赖性的发展。然而，在探索CB 2之间的潜在相互作用时， 大麻素受体（CB 2 R）和μ阿片受体（莫尔）信号传导，我们做出了令人兴奋的发现， 某些CB 2激动剂有效地阻止了对阿片诱导的抗异常性疼痛的耐受性的发展， 在小鼠神经性疼痛模型中的有效性，同时也减弱了伴随的身体依赖性， 慢性吗啡暴露这些发现，如果它们可以被翻译到人类身上， 显著改善阿片类药物的临床使用。在翻译这些发现的过程中，我们将完成 三个具体的目的是更好地了解CB 2和μ阿片受体激动剂如何相互作用，以抑制阿片类药物 宽容和依赖： 目的1：鉴定LY 28282360参与阻止阿片耐受的CB 2表达细胞。我们将 描述负责LY 2828360阻断吗啡耐受性发展的能力的细胞类型 并使用药理学操作和条件删除方法鉴定作用位点。 单独的研究将针对初级传入伤害感受器与小胶质细胞。 目的2：确定CB 2激动剂抑制阿片类药物诱导的身体依赖的条件。 我们将描述负责LY 2828360对阿片类药物依赖的影响的细胞类型，如测量的 使用纳洛酮促使阿片类药物戒断，同时使用药理学操作和条件性 删除方法。单独的研究将针对初级传入伤害感受器与小胶质细胞。 目的3：CB 2 R/莫尔相互作用的机制表征。我们将表征CB 2配体的G 蛋白/抑制蛋白信号传导偏差以及它们的G蛋白活化动力学。我们还将确定， LY 2828360和相关CB 2激动剂激活G蛋白信号传导是由于受体的动力学 约束力最后，如果目的1或2的结果表明莫尔和CB 2 R在同一细胞中相互作用，我们 将表征缓慢和快速信号传导CB 2激动剂之间的CB 2 R/莫尔串扰的差异。 这些目标的完成将充分表征CB 2和阿片受体之间的相互作用在临床前研究中的作用。 和基于细胞的模型。这些研究将有助于确定CB 2激动剂可能在以下方面有用的临床环境： 克服了使用阿片类药物治疗慢性疼痛的两个主要限制。

Despite significant limitations, opioids remain a mainstay for the treatment of severe acute and chronic pain. Two clinically significant limitations that accompany the long-term therapeutic use of opioids are: (1) The development of tolerance (requiring escalating doses of opioid to maintain the desired therapeutic benefit or leading to diminished benefit with constant dose) and (2) Physical dependence (withdrawal symptoms on cessation of opioid use, which are very unpleasant, and seeking their avoidance may increase the risk for opioid addiction). Currently, there are no practical approaches for decreasing opioid tolerance or suppressing the development of physical dependence. However, in exploring potential interactions between CB2 cannabinoid receptor (CB2R) and mu opioid receptor (MOR) signaling, we made the exciting discovery that certain CB2 agonists effectively prevented the development of tolerance to opioid-induced anti-allodynic efficacy in a murine neuropathic pain model, while also blunting the physical dependence that accompanies chronic morphine exposure. These findings, if they can be translated to humans, hold the promise to significantly improve the clinical use of opioids. On the path to translating these findings, we will complete three specific aims to better understand how CB2 and mu opioid receptor agonists interact to suppress opioid tolerance and dependence: Aim 1: Identify the CB2-expressing cells engaged by LY28282360 to prevent opioid tolerance. We will delineate the cell types responsible for the ability of LY2828360 to block development of morphine tolerance and identify site of action using both pharmacological manipulations and a conditional deletion approach. Separate studies will target primary afferent nociceptors vs. microglia. Aim 2: Define the conditions under which CB2 agonists suppress opioid-induced physical dependence. We will delineate the cell types responsible for the effects of LY2828360 on opioid dependence, as measured using naloxone precipitated opioid withdrawal, using both pharmacological manipulations and a conditional deletion approach. Separate studies will target primary afferent nociceptors vs. microglia. Aim 3: Mechanistic characterization of CB2R/MOR interaction. We will characterize CB2 ligands for their G protein/arrestin signaling bias as well as their kinetics of G protein activation. We will also determine if the slow activation of G protein signaling by LY2828360 and related CB2 agonists is due to the kinetics of receptor binding. Finally, if the results of Aims 1 or 2 suggest that MOR and CB2R are interacting in the same cell, we will characterize the differences in CB2R/MOR crosstalk between slowly and rapidly signaling CB2 agonists. Completion of these aims will fully characterize interactions between CB2 and opioid receptors in preclinical and cell-based models. These studies will help define the clinical settings where CB2 agonists may be useful in countering two major limitations on the use of opioids in treating chronic pain.