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病和阿片类药物使用障碍（OUD）的高发病率作斗争。 医学监督下的戒断是管理OUD的重要工具， 发生在非药物阿片类药物使用或激动剂治疗后。突然停用 长期使用阿片类药物会导致严重的多方面戒断综合征，包括以下症状， 疼痛/疼痛、震颤、胃肠道不适、腹泻、躁动以及疼痛敏感性增加 （痛觉过敏）和负面情绪症状如焦虑和易怒。因此，管理阿片类药物 戒断是主要的治疗目标。有令人信服的临床前证据支持阿片类药物 依赖和内源性大麻素（eCB）系统，以及δ-9-四氢大麻酚（THC）和其他 大麻素-1受体（CB 1 R）激动剂可以减少阿片类药物戒断症状。然而，直接CB 1 R 基于激动剂的药物可能产生不良副作用，并已证明有滥用倾向。新 研究表明，通过增加循环eCB间接激动CB 1 R是一种有前途的策略， 它提供了类似的益处，但具有较少的不期望的大麻模拟作用。最近，我们确定了甾醇载体 SCP-2是eCB的结合和转运蛋白，我们合成了一种SCP-2抑制剂 在一些实施例中，eCB传输可以被称为SCPI-1，以阻止eCB传输，从而增加eCB音调。本R21探索性/开发性 应用程序将评估SCPI-1的作用，SCPI-1是一种新型内源性大麻素转运抑制剂， 大鼠阿片类戒断症状的多维模型。我们的主要目标是评估是否 SCPI-1减轻雄性和雌性大鼠自发吗啡戒断症状，并确定 SCPI-1的作用是否通过CB 1 R依赖性机制。阿片类物质的身体依赖性将被诱导 使用吗啡剂量递增和维持程序（阿片样物质依赖组）。第二组将 在相同的时间表下接受盐水注射（非依赖组）。在突然停止 吗啡或盐水给药，我们将在盲法条件下注射SCPI-1或载体，然后评估阿片样物质 戒断症状包括：1）指示戒断的躯体体征（例如，上睑下垂，湿狗抖动 通过定时的行为观察和对笼舍食物的测量， 摄入量和体重; 2）在户外焦虑和易怒等负面情绪症状 场，高架十字迷宫，和瓶刷测试;和3）痛觉过敏，使用von Frey测试的机械性疼痛 灵敏度此外，我们将评估SCPI-1对戒断相关行为的影响是否依赖于CB 1 R 通过在盲法条件下用CB 1 R拮抗剂利莫那班或其载体预处理。次级 该提案的目的是评估SCPI-1的体外代谢稳定性，这是开发该药物的关键组成部分。 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 SCP-2抑制剂作为OUD新靶点的进展。

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.