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个迫切的社会需求，也是NIH HEAL计划的核心。在这里，我们测试的假设，酶N-酰基乙醇胺酸酰胺酶（NAAA）提供了一个新的目标，镇痛药物没有滥用的潜力。NAAA水解棕榈酰乙醇胺（PEA），PEA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抑制剂的实质性抗伤害性特性最近已被国际疼痛研究协会（IASP）进行的临床前文献的荟萃分析所认可，但这些特性背后的细胞底物仍然未知。我们发现，Naaa基因敲除（ko）小鼠（i）与野生型同窝小鼠相比，对福尔马林的伤害反应明显降低;（ii）在慢性压迫性损伤（CCI）模型中未能出现持续的感觉异常。相反，Naaa过表达和Ppara-ko小鼠即使在给予亚阈值福尔马林剂量时也表现出稳健的伤害反应行为。Naaa-ko小鼠对疼痛的敏感性降低并不是发育补偿的结果，因为它可以通过施用NAAA抑制剂ARN 19702来表型模仿。重要的是，ARN 19702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，这表明缺乏奖励特性。这些数据表明，NAAA是发现非成瘾性镇痛药的一个有前途的目标。我们将在两个具体目标中检验这一假设：目标1。NAAA作为镇痛药物发现的分子靶点。将解决三个问题：（1）NAAA抑制剂直接靶向哪些细胞类型？我们将产生细胞特异性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对野生型小鼠背根神经节（DRG）和脊髓（SC）中NAA调节信号的影响。(2)什么样的细胞类型介导NAA调节的抗伤害信号？我们将通过建立细胞特异性PPAR-α-ko小鼠系并在福尔马林和CCI试验中评价其疼痛相关反应及其对NAAA抑制剂的敏感性，来鉴定参与NAAA依赖性信号传导的PPAR-α表达细胞。(3)NAAA抑制剂的药效学特征是否与疼痛治疗的安全有效性相一致？我们将确定ARN 19702是否（i）增强自发性伤害感受，（ii）在重复给药后产生耐受性，以及（iii）表现出奖励和/或成瘾潜力。目标2.开发改进的NAAA抑制剂并检查其作为镇痛剂的功效。需要更好的NAAA抑制剂来评估NAAA在疼痛治疗中的可能作用。我们将结合联合收割机基于计算结构的药物和结构-活性关系研究，以发现具有改善的药效学和药代动力学特性、稳健的镇痛活性和无成瘾潜力的新型药物。