Inhibition of Opioid Tolerance

抑制阿片类药物耐受性

• 批准号: 8756461
• 负责人: Carolyn A Fairbanks
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8756461
• 关键词: Absence of pain sensation; Address; Adverse effects; Agmatine; Agonist; Analgesics; Area; Arginine; Behavior Control; Behavioral; Chronic; Cognitive; Data; Degradation Pathway; Development; Drug Delivery Systems; Enzymes; Evaluation; Functional disorder; Future; Genetic; Glutamate Receptor; Glutamates; Goals; Horns; Hypersensitivity; Individual; Knowledge; Learning; Memory; Metabolic Pathway; Modification; Molecular; Molecular Profiling; Motor; Motor output; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neuraxis; Neuromodulator; Neuronal Plasticity; Neuropathy; Neurotransmitters; Nitric Oxide Synthase; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Process; Publishing; Research; Role; Sensory; Site; Spinal; Spinal Cord; System; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Work; adverse outcome; base; chronic pain; dorsal horn; expectation; gene therapy; improved; in vivo; innovation; motor deficit; neuroadaptation; novel; novel therapeutic intervention; novel therapeutics; prevent; programs; public health relevance; receptor; receptor expression; spatial relationship

DESCRIPTION (provided by applicant): Analgesic tolerance arises with chronic opioid pharmacotherapy. Blockade of NMDA receptors reduces the development of opioid tolerance, but delivery of NMDA receptor antagonists can result in motor and/or cognitive toxicity. Agmatine is a decarboxylated form of L-arginine produced in the central nervous system (CNS) that significantly reduces opioid analgesic tolerance. Although evidence suggests that agmatine antagonizes the NMDA receptor, unlike many synthetic NMDA receptor antagonists delivered spinally, it does not elicit motor deficits. This pharmacological profile suggests that spinally delivered agmatine may act at the NR2B subunit of the NMDA receptor, the expression of which is restricted to the sensory region of the spinal cord and not in the ventral horn. The objective o this application is to define the mechanism by which CNS agmatine modifies behavioral neuroplasticity, evaluate its role as a neuromodulator, and determine the potential of targeting the agmatinergic system as a gene therapy to improve opioid analgesia. The central hypothesis is that CNS agmatine inhibits opioid analgesic tolerance through antagonism of the NMDA receptor and in particular the NR2B-containing NMDA receptors. Three specific aims are proposed: Specific Aim #1: Delineate the contribution of CNS-derived agmatine to inhibition of opioid tolerance. We will address this aim through evaluation of induction of spinal opioid tolerance under conditions of genetic alteration of agmatine's synthetic and degradative enzymes in vivo. Specific Aim #2: Define the mechanism by which CNS-derived agmatine inhibits opioid tolerance. We will address this aim with pharmacological, physiological, and molecular approaches that will test the relationship of agmatine to the glutamatergic system. Specific Aim #3: Determine the impact of opioid tolerance on the agmatinergic system and its target receptor(s). To address this aim, we will use anatomical and molecular approaches. The experimental approach is innovative because it will uncover a largely understudied inhibitory system that opposes maladaptive neuroplasticity. The information acquired will indicate the extent to which endogenous agmatine can be accessed to maximize inhibition of pathological neuroadaptation (e.g. opioid tolerance). The knowledge gained is expected to be useful for management and treatment of chronic pain and directly applicable to other CNS dysfunctions.

描述（由申请人提供）：长期阿片类药物治疗会产生镇痛耐受。阻断 NMDA 受体可减少阿片类药物耐受性的发展，但 NMDA 受体拮抗剂的递送可导致运动和/或认知毒性。胍丁胺是中枢神经系统 (CNS) 中产生的 L-精氨酸的脱羧形式，可显着降低阿片类镇痛耐受性。尽管有证据表明胍丁胺拮抗 NMDA 受体，但与许多脊髓递送的合成 NMDA 受体拮抗剂不同，它不会引起运动缺陷。该药理学特征表明，脊髓递送的胍丁胺可能作用于 NMDA 受体的 NR2B 亚基，该受体的表达仅限于脊髓的感觉区域，而不是腹角。本申请的目的是确定中枢神经系统胍丁胺改变行为神经可塑性的机制，评估其作为神经调节剂的作用，并确定靶向胍丁胺能系统作为改善阿片类镇痛的基因疗法的潜力。核心假设是 CNS 胍丁胺通过拮抗 NMDA 受体，特别是含有 NR2B 的 NMDA 受体来抑制阿片类镇痛耐受。提出了三个具体目标： 具体目标#1：描述中枢神经系统衍生的胍丁胺对抑制阿片类药物耐受性的贡献。我们将通过评估在体内胍丁胺合成酶和降解酶基因改变的条件下诱导脊髓阿片类药物耐受性来实现这一目标。具体目标#2：定义中枢神经系统衍生的胍丁胺抑制阿片类药物耐受的机制。我们将通过药理学、生理学和分子方法来实现这一目标，以测试胍丁胺与谷氨酸能系统的关系。具体目标#3：确定阿片类药物耐受性对无胺能系统及其目标受体的影响。为了实现这一目标，我们将使用解剖学和分子方法。该实验方法是创新的，因为它将揭示一个很大程度上未被充分研究的抑制系统，该系统可以对抗适应不良的神经可塑性。获得的信息将表明可以在多大程度上获得内源性胍丁胺以最大限度地抑制病理性神经适应（例如阿片类药物耐受性）。所获得的知识预计将有助于慢性疼痛的管理和治疗，并直接适用于其他中枢神经系统功能障碍。