The lipid hydrolase NAAA as a target for non-addictive analgesic medications

脂质水解酶 NAAA 作为非成瘾性镇痛药物的靶标

基本信息

批准号：
10584428
负责人：
Daniele Piomelli
金额：
$ 58.53万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584428
关键词：
Acids Acute Acute Pain Address Agonist American Analgesics Animals Attenuated Behavior Brain Cell Lineage Cells Chemicals Collaborations Compensation Cysteine Data Development Dose Dose Limiting Endocannabinoids Enzymes Exhibits FAAH inhibitor Formalin Helping to End Addiction Long-term Hydrolase Injections International Intravenous Knockout Mice Ligands Lipids Literature Mediating Medicine Meta-Analysis Modeling Molecular Target Motivation Mus Neurons Neuropathy Nociception Nuclear Receptors Opioid PPAR alpha Pain Pain management Pathologic Patients Penetration Pharmaceutical Preparations Pharmacodynamics Phenocopy Population Positioning Attribute Property Public Health Publishing Regulation Research Resolution Rewards Risk Role Self Administration Sensory Series Signal Transduction Spinal Cord Spinal Ganglia Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Effect United States National Institutes of Health Wild Type Mouse Work abuse liability addiction amidase antinociception cannabinoid receptor cell type chronic constriction injury chronic pain conditioned place preference design drug discovery experimental study improved inhibitor innovation monocyte nerve injury novel overexpression pain processing palmidrol pharmacokinetics and pharmacodynamics pre-clinical preclinical study response sciatic nerve injury side effect tool transcription factor

Acids Acute Acute Pain Address Agonist American Analgesics Animals Attenuated Behavior Brain Cell Lineage Cells Chemicals Collaborations Compensation Cysteine Data Development Dose Dose Limiting Endocannabinoids Enzymes Exhibits FAAH inhibitor Formalin Helping to End Addiction Long-term Hydrolase Injections International Intravenous Knockout Mice Ligands Lipids Literature Mediating Medicine Meta-Analysis Modeling Molecular Target Motivation Mus Neurons Neuropathy Nociception Nuclear Receptors Opioid PPAR alpha Pain Pain management Pathologic Patients Penetration Pharmaceutical Preparations Pharmacodynamics Phenocopy Population Positioning Attribute Property Public Health Publishing Regulation Research Resolution Rewards Risk Role Self Administration Sensory Series Signal Transduction Spinal Cord Spinal Ganglia Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Effect United States National Institutes of Health Wild Type Mouse Work abuse liability addiction amidase antinociception cannabinoid receptor cell type chronic constriction injury chronic pain conditioned place preference design drug discovery experimental study improved inhibitor innovation monocyte nerve injury novel overexpression pain processing palmidrol pharmacokinetics and pharmacodynamics pre-clinical preclinical study response sciatic nerve injury side effect tool transcription factor

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项目摘要

The discovery of safe and effective analgesics is an urgent societal need and a centerpiece of NIH’s HEAL initiative. Here, we test the hypothesis that the enzyme N-Acylethanolamine Acid Amidase (NAAA) offers a novel target for analgesic medications devoid of abuse potential. NAAA hydrolyzes palmitoylethanolamide (PEA), a lipid messenger that suppresses nociception by engaging the nuclear receptor PPAR-α. The substantial antinociceptive properties of NAAA inhibitors have been recently recognized by a meta-analysis of the preclinical literature conducted by the International Association for the Study of Pain (IASP), but the cellular substrates underlying such properties are still unknown. We found that Naaa-knock out (ko) mice (i) have markedly reduced nocifensive responses to formalin, compared to wild-type littermates; and (ii) fail to develop persistent sensory abnormalities in the chronic constriction injury (CCI) model. Conversely, Naaa- overexpressing and Ppara-ko mice exhibit robust nocifensive behavior even when given a subthreshold formalin dose. The reduced sensitivity of Naaa-ko mice to pain does not result from developmental compensation, because it can be phenocopied by administration of the NAAA inhibitor ARN19702. Importantly, ARN19702 does not exert positive motivational effects in the mouse conditioned place preference (CPP) test, which is suggestive of a lack of rewarding properties. These data point to NAAA as a promising target for the discovery of non-addictive analgesics. We will test this hypothesis in two specific aims: Aim 1. Validate NAAA as a molecular target for analgesic drug discovery. Three questions will be addressed: (1) What cell types are directly targeted by NAAA inhibitors? We will generate cell-specific NAAA-ko mouse lines and evaluate, in the formalin and CCI models, pain-related behaviors and sensitivity to NAAA blockade. In parallel, we will determine the impact of pathological pain on NAAA-regulated signaling in dorsal root ganglia (DRG) and spinal cord (SC) of wild-type mice. (2) What cell types mediate NAAA-regulated antinociceptive signaling? We will identify PPAR-α-expressing cells involved in NAAA-dependent signaling by creating cell-specific PPAR-α-ko mouse lines and evaluating their pain-related responses and their sensitivity to NAAA inhibitors in the formalin and CCI tests. (3) Is the pharmacodynamic profile of NAAA inhibitors compatible with safe and effective use in pain therapy? We will determine whether ARN19702 (i) alleviates spontaneous nociception, (ii) produces tolerance after repeated administration, and (iii) exhibits rewarding and/or addicting potential. Aim 2. Develop improved NAAA inhibitors and examine their efficacy as analgesic agents. Better NAAA inhibitors are needed to assess NAAA’s possible role in pain therapy. We will combine computational structure-based drug and structure-activity relationship studies to discover novel agents with improved pharmacodynamic and pharmacokinetic properties, robust analgesic activity, and no addictive potential.

发现安全有效的镇痛药是紧急的社会需求，也是NIH的HEAD计划的核心。在这里，我们检验了以下假设：N-酰基乙醇胺酸胺（NAAA）为没有滥用潜力的镇痛药提供了一种新颖的靶标。 NAAA水解棕榈酰胺酰胺（PEA），一种脂质信使，通过与核受体PPAR-α接合来抑制Nocetion。最近，通过国际疼痛研究协会（IASP）对临床前文献进行的荟萃分析，NAAA抑制剂的实质性抗感染性特性已被识别，但是这些特性的细胞底物仍然未知。我们发现，与野生型文献相比，NAAA-KNOCK OUT OUT（KO）小鼠（i）对福尔马林的反应显着降低。（ii）在慢性收缩损伤（CCI）模型中未能发展出持续的感觉异常。相反，即使给予福尔马林以下剂量，对NAAA过表达和PPARA-KO小鼠也暴露了强大的单化行为。 NAAA-KO小鼠对疼痛的敏感性降低并不是由于发育补偿而导致的，因为它可以通过施用NaAA抑制剂ARN19702进行表现。重要的是，ARN19702在小鼠条件的位置偏好（CPP）测试中没有执行积极的动机效应，这表明缺乏奖励性能。这些数据表明NAAA是发现非添加性镇痛药的承诺目标。我们将在两个具体目标中检验这一假设：目标1。验证NAAA作为镇痛药发现的分子靶标。将解决三个问题：（1）NAAA抑制剂直接针对哪些细胞类型？我们将在福尔马林和CCI模型，与疼痛相关的行为以及对NAAA封锁的敏感性中生成细胞特异性的NAAA-KO小鼠系和评估。同时，我们将确定病理疼痛对野生型小鼠的背根神经节（DRG）和脊髓（SC）中NAAA调节的信号传导的影响。（2）哪些细胞类型介导了NAAA调节的抗伤害感受信号传导？我们将通过创建细胞特异性的PPAR-α-KO小鼠系，评估其与疼痛相关的反应以及对福尔马林和CCI测试中NAAA抑制剂的敏感性，从而确定参与NAAA依赖性信号传导的表达PPAR-α的细胞。（3）NAAA抑制剂的药效学特征是否与安全有效地兼容疼痛治疗？我们将确定ARN19702（i）是否减轻了赞助伤害感，（ii）在重复给药后产生耐受性，（iii）具有奖励和/或上瘾的潜力。目标2。发展改善的NAAA抑制剂并检查其作为镇痛药的有效性。需要更好的NAAA抑制剂来评估NAAA在疼痛疗法中的可能作用。我们将结合基于计算结构的药物和结构活性研究研究，以发现具有改进的药效和药代动力学特性，鲁棒镇痛活性和无添加剂潜力的新型药物。