Inhibition of Opioid Tolerance

抑制阿片类药物耐受性

• 批准号: 9066132
• 负责人: Carolyn A Fairbanks
• 金额: $ 33.86万
• 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/9066132
• 关键词: 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; Health; 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; 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; neuroregulation; novel; novel therapeutic intervention; opiate tolerance; opioid use; prevent; programs; receptor; receptor expression; sensory input; 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(申请人提供)：慢性阿片类药物治疗会产生止痛耐受。阻断NMDA受体可减少阿片耐受性的形成，但NMDA受体拮抗剂的应用可导致运动和/或认知毒性。胍丁胺是中枢神经系统产生的L精氨酸的脱羧基形式，可显著降低阿片类止痛耐受性。尽管有证据表明，胍丁胺能拮抗NMDA受体，但与许多合成的NMDA受体拮抗剂不同，它不会导致运动障碍。这一药理学特征表明，脊髓递送的胍丁胺可能作用于NMDA受体的NR2B亚单位，该亚单位的表达仅限于脊髓的感觉区域，而不是腹角。这一应用的目的是明确CNS胍丁胺改变行为神经可塑性的机制，评价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药物镇痛的基因治疗的可能性。中心假说是，CNS胍丁胺通过拮抗NMDA受体，特别是含有NR2B的NMDA受体来抑制阿片类止痛耐受。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耐受性的贡献。我们将通过评估体内胍丁胺合成酶和降解酶的基因改变条件下脊髓阿片类药物耐受的诱导来解决这一目标。具体目标2：确定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测试胍丁胺与谷氨酸能系统的关系，以实现这一目标。具体目标#3：确定阿片耐受对苷胺能系统及其靶受体的影响(S)。为了达到这个目的，我们将使用解剖学和分子方法。实验方法是创新的，因为它将揭示一个很少被研究的抑制系统，该系统反对适应不良的神经可塑性。所获得的信息将表明内源性胍丁胺可在多大程度上最大限度地抑制病理性神经适应(如阿片类药物耐受)。所获得的知识有望对慢性疼痛的管理和治疗有用，并直接适用于其他中枢神经系统功能障碍。