Preclinical assessment of a Sterol Carrier Protein-2 inhibitor in multidimensional opioid withdrawal.

美国仍在与阿片类药物流行和高阿片类药物使用障碍(OUD)作斗争。 有医学监督的戒断是管理OUD的重要工具，在那里阿片类药物停止使用 直接由非药物阿片类药物使用或在激动剂治疗后发生。突然中断 长期使用阿片类药物会导致严重的多维戒断综合征，包括以下症状 疼痛/疼痛、震颤、胃肠道不适、腹泻、躁动以及疼痛敏感度增加 (痛觉过敏)，以及焦虑和易怒等负面情绪症状。因此，管理阿片类药物 停药是主要的治疗目标。有令人信服的临床前证据支持阿片类药物与 依赖与内源性大麻素(ECB)系统、β-9-四氢大麻酚(THC)等 大麻素-1受体(CB1R)激动剂可以减轻阿片类药物的戒断症状。然而，直接CB1R 以激动剂为基础的药物可能会产生不良副作用，并已证明有滥用倾向。新的 研究表明，通过增加循环ECB间接激活CB1R是一个很有前途的策略，因为 它提供了类似的好处，但不良的大麻仿制效果较少。最近，我们测定了甾醇载体 蛋白-2(SCP-2)是ECB的结合和运输蛋白，我们合成了一种SCP-2抑制剂 (SCPI-1)，以阻止欧洲央行的传输，从而增加欧洲央行的语气。本R21探索性/开发性 应用程序将评估SCPI-1，一种新型的内源性大麻素转运抑制剂的效果 大鼠阿片类药物戒断症状的多维模型。我们的主要目标是评估 SCPI-1减轻雄性和雌性大鼠自发吗啡戒断症状 SCPI-1是否通过CB1R依赖机制发挥作用。会导致阿片类物质的身体依赖 使用吗啡剂量递增和维持程序(阿片依赖组)。第二组将 在相同的时间内接受生理盐水注射(非依赖组)。在突然中断后 吗啡或生理盐水剂量，我们将在盲目条件下注射SCPI-1或载体，然后评估阿片类药物 戒断症状包括：1)表明戒断的躯体体征(例如，上睑下垂、湿狗抖动、 通过家庭笼养食品的定时行为观察和测量) 摄入量和体重；2)在露天时焦虑和易怒的负面情绪症状 现场、高架迷宫和瓶刷试验；以及3)使用von Frey机械痛试验的痛觉过敏 敏感度。此外，我们将评估SCPI-1对戒断相关行为的影响是否依赖于CB1R 通过CB1R拮抗剂利莫那班或其载体在盲目条件下进行预处理。次要的 这项建议的目的是评估SCPI-1的体外代谢稳定性，这是开发这一技术的关键组成部分 铅化合物。总体而言，本研究将评估SCPI-1治疗阿片类药物戒断的疗效 作为OUD新靶点的SCP-2抑制剂的症状和药物进展。

The United States is still struggling with an opioid epidemic and high rates of opioid use disorder (OUD). Medically supervised withdrawal is an important tool in management of OUD, where opioid discontinuation occurs either directly from nonmedical opioid use or following agonist treatment. Abrupt discontinuation of chronic opioid use results in a severe, multidimensional withdrawal syndrome that includes symptoms such as aches/pain, tremors, gastrointestinal distress, diarrhea, restlessness, as well as increased pain sensitivity (hyperalgesia), and negative emotional symptoms such as anxiety and irritability. Therefore, managing opioid withdrawal is a primary treatment goal. There is compelling preclinical evidence supporting a link between opioid dependence and the endocannabinoid (eCB) system, and delta-9-tetrahydrocannabinol (THC) and other cannabinoid-1 receptor (CB1R) agonists can reduce opioid withdrawal symptoms. However, direct CB1R agonist-based medications can produce adverse side effects and have demonstrated abuse liability. New research suggests that indirect agonism of CB1R through increasing circulating eCBs is a promising strategy as it confers similar benefits with fewer undesirable cannabimimetic effects. Recently, we determined sterol carrier protein-2 (SCP-2) acts as a binding and transport protein for eCBs and we have synthesized an SCP-2 inhibitor (SCPI-1) to block eCB transport and thereby increase eCB tone. This R21 Exploratory/Developmental application will evaluate the effects of SCPI-1, a novel endocannabinoid transport inhibitor using a multidimensional model of opioid withdrawal symptoms in rats. Our Primary Aim is to evaluate whether SCPI-1 attenuates symptoms of spontaneous morphine withdrawal in male and female rats and determine whether effects of SCPI-1 are via CB1R-dependent mechanisms. Opioid physical dependence will be induced using a morphine dose escalation and maintenance procedure (opioid dependent group). A second group will receive saline injections under the same schedule (non-dependent group). Following abrupt discontinuation of morphine or saline dosing, we will inject SCPI-1 or vehicle under blinded conditions and then assess opioid withdrawal symptoms that include: 1) somatic signs indicative of withdrawal (e.g., ptosis, wet-dog shakes, grooms, hypophagia and weight loss) through timed behavioral observations and measures of home cage food intake and body weights; 2) negative emotional symptoms of anxiety- and irritability- like behavior in the open field, elevated plus maze, and bottle brush test; and 3) hyperalgesia using the von Frey test of mechanical pain sensitivity. In addition, we will evaluate if effects of SCPI-1 on withdrawal-related behaviors are CB1R-dependent through pretreatment with the CB1R antagonist rimonabant or its vehicle under blinded conditions. A Secondary Aim of this proposal is to evaluate the metabolic stability of SCPI-1 in vitro, a key component of developing this lead compound. Overall, this research will evaluate efficacy of SCPI-1 for treatment of opioid withdrawal symptoms and advance medications development of SCP-2 inhibitors as a novel target for OUD.