Stemming the opioid-induced pain cascade via cannabinoid modulation

尽管阿片类药物有滥用的可能性，但它们仍然是止痛药的黄金标准。其中一个较小的 讨论的长期使用阿片类药物的影响是阿片类药物诱导的痛觉过敏（OIH），或增加疼痛 一些用户的敏感性。OIH的持续时间比阿片类药物戒断更长，并且可能 导致药物使用障碍患者的药物寻求和复发。的 OIH的生理原因是由（1）重复的μ阿片样物质激活和脱敏， 和（2）通过吗啡与Toll样受体4的结合激活炎症途径。 大麻素具有良好的镇痛和抗炎特性。内源 大麻素（即，内源性大麻素）具有抗炎作用， 与外源性大麻素相比，拟议的研究将使用一个 重复吗啡暴露的实验动物模型，随后是爪切口损伤。我们 目的是检验内源性大麻素分解代谢酶的抑制 单酰基甘油脂肪酶（MAGL）可减少由反复 吗啡治疗雄性和雌性小鼠将重复施用吗啡或媒介物， 在内源性大麻素浓度增加的情况下，持续四天。内源性大麻素的音调将是 通过MAGL的化学抑制或MAGL的遗传缺失而增加， 只有神经元。然后，在足底表面做一个小切口并缝合， 一只后爪，以模拟术后痛觉过敏。老鼠会被反复测试疼痛- 诱导、疼痛抑制和疼痛条件反射行为模型。内源性大麻素受体 将使用选择性CB 1和CB 2大麻素受体拮抗剂来确定机制。 将收集爪组织以定量促炎细胞因子水平和单个细胞因子 水平将与疼痛相关的行为相关。的抗炎机制 内源性大麻素调节将进一步探讨在体外，使用分离的 巨噬细胞/单核细胞。临床前OIH模型的现有研究使用雄性动物 几乎完全。因为女性可能会增加患OIH的风险，我们将 包括足够数量的雌性和雄性小鼠，以研究性别作为生物学指标， 变量除了增加对潜在的神经和 免疫机制，有助于阿片类药物诱导的痛觉过敏，我们的翻译 研究目标是开发药物滥用障碍的治疗方法。

Despite their abuse potential, opioids remain a gold standard analgesic. One of the lesser discussed effects of chronic opioid use is opioid induced hyperalgesia (OIH), or increased pain sensitivity in some users. OIH persists for a longer duration than opioid withdrawal and may contribute to drug seeking and relapse in people with substance use disorders. The physiological causes of OIH are caused by (1) repeated µ opioid activation and desensitization, and (2) activation of inflammatory pathways by morphine binding to Toll-like receptor 4. Cannabinoids have well established analgesic and anti-inflammatory properties. Endogenous cannabinoids (i.e., endocannabinoids) have anti-inflammatory effects with limited intoxicating effects, as compared with exogenous cannabinoids. The proposed study will use an experimental animal model of repeated morphine exposure, followed by paw incision injury. Our goal is to test the hypothesis that inhibition of the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL) decreases pain and inflammation caused by repeated morphine treatment. Male and female mice will be repeatedly administered morphine or vehicle, in the presence of increased endocannabinoid tone, for four days. Endocannabinoid tone will be increased by either chemical inhibition of MAGL, or genetic deletion of MAGL globally or on neurons only. Then, a small incision will be made and sutured closed in the plantar surface of one hindpaw, to model postoperative hyperalgesia. Mice will be tested repeatedly for pain- induced, pain-suppressed, and pain conditioning behavioral models. Endocannabinoid receptor mechanism will be determined using selective CB1 and CB2 cannabinoid receptor antagonists. Paw tissue will be collected to quantify proinflammatory cytokine levels, and individual cytokine levels will be correlated with pain-related behaviors. The anti-inflammatory mechanisms of endocannabinoid modulation will be further probed in vitro, using isolated macrophages/monocytes. Extant studies of preclinical OIH models have used male animals almost exclusively. Because women may be at increased risk for developing OIH, we will include sufficient numbers of both female and male mice to investigate Sex as a Biological Variable. In addition to increasing basic understanding of the underlying neural and immunological mechanisms that contribute to opioid-induced hyperalgesia, our translational research goal is to develop treatments for substance abuse disorders.