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

甾醇载体蛋白 2 抑制剂在多维阿片类药物戒断中的临床前评估。

• 批准号: 10671726
• 负责人: CHRISTOPHER W CUNNINGHAM
• 金额: $ 20.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671726
• 关键词: Abstinence; Ache; Agitation; Agonist; Animal Model; Anti-Anxiety Agents; Anxiety; Attenuated; Behavior; Binding; Binding Proteins; Blinded; Body Weight; Body Weight decreased; CNR1 gene; Canis familiaris; Carrier Proteins; Cessation of life; Chronic; Control Groups; Data; Development; Diarrhea; Dimensions; Distress; Dose; Drug usage; Eating; Endocannabinoids; Female; Future; Goals; Grooming; Half-Life; Helping to End Addiction Long-term; Home; Hyperalgesia; In Vitro; Individual; Injections; Intracellular Transport; Lead; Link; Lipid Binding; Maintenance; Mechanics; Mediating; Medical; Medication Management; Metabolic; Modeling; Morphine; National Institute of Drug Abuse; Opiate Addiction; Opioid; Pain; Persons; Pharmaceutical Preparations; Physical Dependence; Procedures; Ptosis; Public Health; Rattus; Research; Research Project Grants; Rodent; SCP 1; Saline; Schedule; Severities; Strategic Planning; Substance Withdrawal Syndrome; Symptoms; Testing; Tetrahydrocannabinol; Tremor; United States; United States National Institutes of Health; Withdrawal; Withdrawal Symptom; abuse liability; antagonist; anxiety symptoms; behavior measurement; behavior observation; cannabimimetics; economic cost; efficacy evaluation; emotional behavior; emotional symptom; endogenous cannabinoid system; experimental study; gastrointestinal; inhibitor; male; motor impairment; natural hypothermia; non-opioid analgesic; non-specific lipid transfer protein; novel; opioid epidemic; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; pain sensitivity; pre-clinical; pre-clinical assessment; rimonabant; side effect; therapeutic development; therapeutic target; tool; transport inhibitor

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.

美国仍在与阿片类药物泛滥和阿片类药物使用障碍 (OUD) 发生率高的问题作斗争。 医学监督戒断是 OUD 管理的重要工具，其中阿片类药物停药 直接因非医疗阿片类药物使用或激动剂治疗后发生。突然停止 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、震颤、胃肠道不适、腹泻、烦躁不安以及疼痛敏感性增加 （痛觉过敏）和负面情绪症状，例如焦虑和烦躁。因此，管理阿片类药物 戒断是主要治疗目标。有令人信服的临床前证据支持阿片类药物之间的联系 依赖和内源性大麻素（eCB）系统，以及δ9-四氢大麻酚（THC）和其他 大麻素 1 受体 (CB1R) 激动剂可以减轻阿片类药物戒断症状。然而，直接CB1R 基于激动剂的药物可能会产生不良副作用，并已证明存在滥用倾向。新的 研究表明，通过增加循环 eCB 来间接激动 CB1R 是一种有前途的策略，因为 它具有类似的好处，但不良的大麻模拟作用更少。最近，我们确定了甾醇载体 Protein-2 (SCP-2) 作为 eCB 的结合和转运蛋白，我们合成了一种 SCP-2 抑制剂 (SCPI-1) 阻止 eCB 传输，从而增加 eCB 音调。 R21 探索性/开发性 应用程序将评估 SCPI-1 的效果，SCPI-1 是一种新型内源性大麻素转运抑制剂，使用 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 的作用是否是通过 CB1R 依赖性机制产生的。会诱发阿片类药物身体依赖性 使用吗啡剂量递增和维持程序（阿片类药物依赖组）。第二组将 在相同的时间表下接受盐水注射（非依赖组）。突然停止后 吗啡或盐水剂量，我们将在盲法条件下注射 SCPI-1 或媒介物，然后评估阿片类药物 戒断症状包括：1）表明戒断的躯体症状（例如上睑下垂、湿狗颤抖、 通过定时行为观察和家庭笼内食物测量来预防新郎、吞咽不足和体重减轻 摄入量和体重； 2）在公开场合表现出焦虑和烦躁等负面情绪症状 野外、高架十字迷宫和瓶刷测试； 3) 使用冯弗雷机械疼痛测试的痛觉过敏 敏感性。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 通过在盲法条件下用 CB1R 拮抗剂利莫那班或其载体进行预处理。二级 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新靶标的症状和推进药物开发。