CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence

尽管有很大的局限性，阿片类药物仍然是治疗严重急性和慢性疼痛的主要药物。 长期使用阿片类药物在临床上有两个显著的局限性：(1) 形成耐受性(需要增加阿片类药物的剂量以维持预期的治疗效果或 (2)身体依赖(戒断症状 停止使用阿片类药物，这是非常令人不快的，寻求避免使用阿片类药物可能会增加患上 阿片成瘾)。目前，没有减少阿片类药物耐受性或抑制的实际方法。 身体依赖的发展。然而，在探索CB2之间潜在的相互作用时 大麻素受体(CB2R)和单位阿片受体(MOR)的信号转导，我们有了令人兴奋的发现 某些CB2激动剂有效地阻止了阿片类药物诱导的止痛耐受性的发展 在小鼠神经病理性疼痛模型中的有效性，同时也钝化伴随而来的身体依赖 长期接触吗啡。这些发现，如果能被翻译到人类身上，就有望 显著提高阿片类药物的临床使用水平。在翻译这些发现的道路上，我们将完成 为了更好地了解CB2和MU阿片受体激动剂如何相互作用抑制阿片类药物，有三个具体目标 宽容和依赖： 目的1：鉴定LY28282360参与预防阿片耐受的CB2表达细胞。我们会 LY2828360阻断吗啡耐受形成的细胞类型 并使用药理操作和条件删除方法来识别作用部位。 单独的研究将针对初级传入伤害性感受器和小胶质细胞。 目的2：确定CB2激动剂抑制阿片类药物身体依赖的条件。 我们将描述LY2828360对阿片类药物依赖的影响的细胞类型 使用纳洛酮催促阿片类药物戒断，使用药物操作和条件 删除方法。单独的研究将针对初级传入伤害性感受器和小胶质细胞。 目的3：CB2R/MOR相互作用的机制表征。我们将表征CB2配体的G 蛋白质/arrestin信号偏向及其G蛋白激活动力学。我们还将确定缓慢的 LY2828360及其相关的CB2激动剂激活G蛋白信号是由于受体的动力学 有约束力的。最后，如果目标1或2的结果表明MOR和CB2R在同一细胞中相互作用，我们 将表征慢速和快速信号CB2激动剂在CB2R/MOR串扰方面的差异。 这些目标的完成将充分描述临床前CB2和阿片受体之间的相互作用 和基于细胞的模型。这些研究将有助于确定CB2激动剂在哪些临床环境中可能有用 消除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.