Stemming the opioid-induced pain cascade via cannabinoid modulation

尽管阿片类药物有滥用潜力，但它仍然是一种黄金标准的止痛药。较小的一个 讨论了长期使用阿片类药物的影响是阿片类药物诱发的痛觉过敏(OIH)，或疼痛加剧 一些用户的敏感度。OIH持续的时间比阿片类药物戒断更长，可能 在有药物使用障碍的人中，有助于寻求毒品和复发。这个 OIH的生理原因是：(1)阿片类药物反复激活和脱敏， 以及(2)通过吗啡与Toll样受体4结合而激活炎症通路。 大麻素具有良好的止痛和抗炎特性。内生性 大麻素(即内源性大麻素)具有抗炎作用，但醉人作用有限。 与外源大麻素相比，其影响更大。拟议的研究将使用 建立反复吗啡暴露、爪部切开损伤的实验动物模型。我们的 目的是验证抑制内源性大麻素分解代谢酶的假设 单酰基甘油脂肪酶(MAGL)可减轻反复发作引起的疼痛和炎症 吗啡治疗。雄性和雌性小鼠将反复给予吗啡或交通工具， 在内源性大麻素增加的情况下，连续四天。内源性大麻素的色调将是 由于MAGL的化学抑制或MAGL的基因全局或基因缺失而增加 仅限神经元。然后，在足底表面做一个小切口，闭合缝合。 一只后爪，模拟术后痛觉过敏。老鼠将反复接受疼痛测试- 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 机制将使用选择性CB1和CB2大麻素受体拮抗剂来确定。 将收集爪子组织以量化促炎症细胞因子水平，以及单个细胞因子 这一水平将与疼痛相关的行为相关。银杏叶提取物的抗炎机制 内源性大麻素的调节将在体外进一步探索，使用分离的 巨噬细胞/单核细胞。现有的临床前OIH模型的研究使用了雄性动物 几乎是独一无二的。因为女性患OIH的风险可能会增加，我们将 包括足够数量的雌性和雄性小鼠来研究性作为生物 变量。除了增加对潜在神经和神经的基本了解 导致阿片类药物引起痛敏的免疫学机制，我们的翻译 研究目标是开发治疗药物滥用障碍的方法。

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.