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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管研究人员努力寻找替代方法，但意外过量死亡仍定义为阿片类药物流行病解决阿片类药物使用障碍 [1] 和替代慢性疼痛疗法 [2]。据报告，自 1999 年以来已有超过 400,000 人丧生，每天有 130 多人因意外服药过量而丧生 [3] 随着处方阿片类药物的过度使用和阿片类药物的存在，这一数字将继续攀升。非法市场上更强的合成阿片类药物可以成功解决潜在致命的阿片类药物过量问题。纳洛酮（μ阿片受体拮抗剂）可以逆转这种情况，[7]，但疼痛患者的数量不断增加心脏病和糖尿病 [2] 以及芬太尼在非法阿片类药物市场中的存在增加，足以在发生缺氧之前分配纳洛酮以逆转药物过量仍然很困难[8]。使用新型阿片类化合物减少阿片类药物过量的方法基本上不成功[9]。至关重要的是，尚未探索的治疗策略可以预防阿片类药物引起的呼吸抑制发现了。致命的阿片类药物过量通常归因于呼吸抑制，在此期间，呼吸抑制我们的试验数据表明，脑干中控制反射性吸气的前波辛格复合体 (pBc) 受到抑制。 1) 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) 脂质激活 CB2R 对于正常呼吸至关重要控制，3) CB2R 激动剂的外源性应用减轻吗啡引起的呼吸抑制。当前的提案将建立在这些发现的基础上，利用行为药理学、全身体积描记法、成像、分子生物学、分析化学和基因编辑来检验以下假设：阿片类药物引起的呼吸抑制期间 pBc 中的内源性大麻素水平降低 (OIRD) 并且脑渗透性 CB2R 激动剂的施用将减轻 OIRD 目标 1 将测试 CB2R。每个目标都包含合理设计的研究，其中包括性。通过纳入雄性和雌性小鼠的差异，应用于急性和慢性药物使用和娱乐性阿片类药物（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 将确定内脂大麻素、酶和受体的水平。 OIRD 期间的 preBotzinger 复合体 (pBc) 的成功完成将有助于增强我们对正常呼吸期间和 OIRD 期间 ECBS 在 pBc 内的作用的了解并验证 CB2R 作为一种安全的治疗方法，以减少阿片类药物过量。