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

• 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
• 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

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一项紧迫的社会需求，也是 NIH HEAL 计划的核心内容。在这里，我们测试了 N-酰基乙醇胺酸性酰胺酶 (NAAA) 为没有滥用可能性的镇痛药物提供了一个新靶点的假设。水解棕榈酰乙醇酰胺 (PEA)，这是一种脂质信使，通过与核受体 PPAR-α 结合来抑制伤害感受 NAAA 的显着镇痛特性。最近，国际疼痛研究协会 (IASP) 进行的临床前文献荟萃分析已经认识到了 Naaa 抑制剂的作用，但我们发现 Naaa 敲除 (ko) 小鼠的这种特性的细胞底物仍然未知。 (i) 与野生型同窝小鼠相比，对福尔马林的伤害反应显着降低；并且 (ii) 在离线、Naaa 过度表达和慢性缩窄性损伤 (CCI) 模型中未出现持续性感觉异常。即使给予阈值以下的福尔马林剂量，Ppara-ko 小鼠也表现出强烈的伤害行为。Naaa-ko 小鼠对疼痛的敏感性降低并不是由发育补偿引起的，因为它可以通过施用 NAAA 抑制剂 ARN19702 来复制。重要的是，ARN19702 确实如此。在小鼠条件性位置偏好 (CPP) 测试中没有发挥积极的激励作用，这表明 NAAA 缺乏奖励特性。我们将在两个具体目标中检验这一假设： 目标 1. 验证 NAAA 作为镇痛药物发现的分子靶点：(1) 哪些细胞类型是其直接靶向的。 NAAA 抑制剂？我们将生成细胞特异性 NAAA-ko 小鼠系，并在福尔马林和 CCI 模型中评估疼痛相关行为和对 NAAA 阻断的敏感性。同时，我们将确定病理性疼痛的影响。野生型小鼠背根神经节 (DRG) 和脊髓 (SC) 中 NAAA 调节的信号传导 (2) 哪些细胞类型介导 NAAA 调节的抗伤害感受信号传导？ (3) NAAA抑制剂的药效学特征是否兼容目标 2. 开发改进的 NAAA 抑制剂和需要更好的 NAAA 抑制剂来评估 NAAA 在疼痛治疗中的可能作用，我们将进行基于计算结构的药物和结构-活性关系研究，以发现具有改善药效的新型药物。和药代动力学特性，强大的镇痛活性，并且无成瘾潜力。