Inhibition of Opioid Tolerance

描述（由申请人提供）：慢性阿片类药物治疗引起镇痛耐受。阻断NMDA受体可减少阿片耐受性的发展，但NMDA受体拮抗剂的递送可导致运动和/或认知毒性。胍丁氨酸是一种在中枢神经系统（CNS）中产生的l -精氨酸的脱羧形式，可显著降低阿片类镇痛药耐受性。虽然有证据表明，胍丁氨酸可以拮抗NMDA受体，但与许多经脊髓传递的合成NMDA受体拮抗剂不同，它不会引起运动缺陷。这一药理特征表明，脊髓传递的胍丁氨酸可能作用于NMDA受体的NR2B亚基，该亚基的表达仅限于脊髓的感觉区，而不是在腹角。本应用的目的是确定中枢神经系统agmatinine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agmatinerg能系统作为基因治疗改善阿片类镇痛的潜力。中心假设是中枢神经系统的胍丁氨酸通过拮抗NMDA受体，特别是nr2b -含NMDA受体抑制阿片样镇痛耐受。具体目标#1：描述中枢神经系统衍生的agmatine对阿片耐受性抑制的贡献。我们将通过评估在体内agmatine合成和降解酶基因改变的条件下脊髓阿片耐受性的诱导来解决这一问题。具体目标#2：确定中枢神经系统衍生的胍丁氨酸抑制阿片耐受性的机制。我们将用药理学、生理学和分子方法来解决这个问题，这些方法将测试谷氨酸与谷氨酸系统的关系。具体目标#3：确定阿片类药物耐受性对凝集能系统及其靶受体的影响。为了解决这个问题，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大程度上未被充分研究的抑制系统，以对抗神经可塑性不良。获得的信息将表明内源性胍丁氨酸可以在多大程度上最大限度地抑制病理性神经适应（如阿片耐受性）。所获得的知识有望用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。

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.