Endocannabinoid Targeting for Opioid Induced Respiratory Depression

内源性大麻素靶向治疗阿片类药物引起的呼吸抑制

• 批准号: 10508272
• 负责人: Tally Marie Milnes
• 金额: $ 164.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508272
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Acute; Acute Pain; Address; Adverse effects; Agonist; Analytical Chemistry; Animals; Area; Attenuated; Behavior; Binding; Blood gas; Brain; Brain Stem; Breathing; CNR2 gene; Cannabinoids; Carbon Dioxide; Cell Nucleus; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chronic; Clinical; Clinical Treatment; Clinical Trials; Cocaine; Constipation; Data; Development; Diabetes Mellitus; Dose; Drowsiness; Endocannabinoids; Enzymes; Ethanol; Female; Fentanyl; Foundations; G-Protein-Coupled Receptors; Genes; HIV; Heart Diseases; Helping to End Addiction Long-term; Heroin; Human; Hyperesthesia; Hypersensitivity; Image; Immune system; Immunohistochemistry; Impaired cognition; Inflammation; Knock-out; Knowledge; Lead; Life; Lipids; Literature; Malignant Bone Neoplasm; Measures; Mechanics; Molecular Biology; Morphine; Morphine Derivatives; Multiple Sclerosis; Mus; Naloxone; Neuraxis; Neuroglia; Neurons; Neuropathy; Nicotine; Non-Steroidal Anti-Inflammatory Agents; Opioid; Opioid Antagonist; Opioid agonist; Overdose; Overdose reversal; Oxycodone; Oxygen; Persons; Pharmaceutical Preparations; Physiology; Play; Pre-Clinical Model; Proteomics; Publishing; Pulmonary Edema; Pulse Oximetry; Receptor Activation; Reflex control; Regulation; Reporting; Research; Research Design; Respiration; Rewards; Role; Sex Differences; System; Testing; Therapeutic; Tidal Volume; Toxic effect; Ventilatory Depression; Whole Body Plethysmography; addiction; anandamide; antagonist; behavioral pharmacology; behavioral study; cancer pain; chemotherapy induced neuropathy; chronic pain; chronic pain management; clinical outcome measures; comorbidity; cost; deprivation; design; drug discovery; drug of abuse; endogenous cannabinoid system; experimental study; illicit opioid; inflammatory pain; innovation; liquid chromatography mass spectrometry; male; mu opioid receptors; new therapeutic target; novel; opioid epidemic; opioid exposure; opioid overdose; opioid overuse; opioid sparing; opioid therapy; opioid use; opioid use disorder; overdose death; pain inhibition; pain patient; peptidomimetics; polysubstance use; preBotzinger complex; prescription opioid; prescription opioid abuse; prevent; programs; rational design; receptor; respiratory; response; side effect; small molecule; spontaneous pain; synthetic enzyme; synthetic opioid; therapeutic development; ventilation

Project Summary Accidental overdoses fatalities define the opioid epidemic despite research efforts for alternative means to address Opioid Use Disorder [1] and alternative chronic pain therapies [2]. The Centers for Disease Control report over 400,000 lives lost since 1999 and more than 130 people lose their life to an accidental overdose daily [3]. This number will continue to climb with excessive utilization of prescription opioids and the presence of stronger synthetic opioids in the illicit market [4-6]. A potentially fatal opioid overdose can be successfully reversed with naloxone, mu opioid receptor antagonist, [7], but with the number of pain patients rising above heart disease and diabetes [2] and the increased presence of fentanyl in the illicit opioid market, adequate distribution of naloxone to reverse an overdose before oxygen deprivation occurs remains difficult [8]. Attempts to reduce opioid overdoses with novel opioid-like compounds have been largely unsuccessful [9]. Therefore, it is essential that unexplored therapeutic strategies to prevent opioid-induced respiratory depression be discovered. Fatal opioid overdoses are typically attributed to respiratory depression, during which neurons within the preBötzinger complex (pBc) in the brainstem that control reflexive inspiration are inhibited. Our pilot data suggest that 1) the pBc contains the components of the endocannabinoid system, including the cannabinoid receptor 2 (CB2R), 2) CB2R activation by endogenous cannabinoid system (ECBS) lipids is critical to normal respiration control, and 3) exogenous application of a CB2R agonist mitigates morphine induced respiratory depression. The current proposal will build upon these findings, using behavioral pharmacology, whole body plethysmography, imaging, molecular biology, analytical chemistry, and gene-editing to test the hypothesis that endogenous cannabinoid levels in the pBc are reduced during opioid induced respiratory depression (OIRD) and that administration of a brain penetrant CB2R agonist will mitigate OIRD. Aim 1 will test CB2R agonism as a strategy to mitigate to OIRD. Each aim contains rationally designed studies that include sex differences through inclusion of male and female mice, application to both acute and chronic use of medicinal and recreational opioids (fentanyl, oxycodone, and heroin), and multiple chemical classes of CB2R agonists to prevent and reverse OIRD. Aim 2 will determine levels of endocannabinoid lipids, enzymes, and receptors in the preBotzinger complex (pBc) during OIRD. Successful completion of proposed studies will serve to enhance our knowledge of the role of ECBS within the pBc in during normal respiration and during OIRD and validate targeting the CB2R as a safe treatment therapeutic to reduce opioid overdoses.

项目摘要 意外过量死亡定义了阿片类药物的流行，尽管研究努力寻找替代方法 解决阿片类药物使用障碍[1]和替代慢性疼痛疗法[2]。疾病控制中心 报告称，自1999年以来，有40多万人丧生，每天有130多人死于意外服药过量 [3]。随着处方类阿片类药物的过度使用和 非法市场上更强的合成阿片类药物[4-6]。一种可能致命的阿片类药物过量可以成功 用Mu阿片受体拮抗剂纳洛酮逆转[7]，但随着疼痛患者数量的增加 心脏病和糖尿病[2]以及非法阿片类药物市场上芬太尼的增加，足够 在缺氧发生之前，分配纳洛酮以逆转过量仍然很困难[8]。尝试 使用新的阿片类化合物减少阿片类药物过量在很大程度上是不成功的[9]。因此，它 至关重要的是，预防阿片类药物引起的呼吸抑制的未探索的治疗策略 被发现了。 致命的阿片类药物过量通常归因于呼吸抑制，在此期间，大脑中的神经元 脑干中控制反射吸气的Prebötzinger复合体(PBC)被抑制。我们的试点数据表明 PBC含有内源性大麻素系统的成分，包括大麻素受体2 (CB2R)，2)内源性大麻素系统(ECBS)脂类激活CB2R对正常呼吸至关重要 外源性应用CB2R激动剂可减轻吗啡引起的呼吸抑制。 目前的建议将建立在这些发现的基础上，使用行为药理学，全身 体积描记、成像、分子生物学、分析化学和基因编辑，以检验这一假设 在阿片类药物诱导的呼吸抑制期间，外周血中内源性大麻素水平降低 (OIRD)和脑渗透性CB2R激动剂的管理将减轻OIRD。AIM 1将测试CB2R 激励性作为一种缓解OIRD的策略。每个目标都包含合理设计的研究，其中包括性行为 通过纳入雄性和雌性小鼠的差异，应用于急性和慢性使用药物 和娱乐类阿片(芬太尼、羟考酮和海洛因)，以及多种化学类别的CB2R激动剂 预防和逆转OIRD。目标2将测定内源性大麻素类脂类、酶和受体的水平 OIRD期间的前博辛格复合体(PBC)。成功完成拟议的研究将有助于 加强我们对体外循环中ECB在正常呼吸期间和OIRD期间的作用的认识 并验证靶向CB2R是一种安全的治疗方法，可以减少阿片类药物过量。

项目成果

The endocannabinoid system and breathing.

• DOI: 10.3389/fnins.2023.1126004
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Wiese, Beth M.;Reyes, Angelica Alvarez;Vanderah, Todd W.;Largent-Milnes, Tally M.
• 通讯作者: Largent-Milnes, Tally M.