Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain

项目概述/摘要：本申请涉及广泛的挑战领域（15）转化科学和特定挑战主题15- NS-103神经疾病新治疗方法的“概念验证”演示。神经性疼痛仍然难以治愈，尽管目前可用的治疗药物的治疗。因此，有必要寻找能够有效减轻神经性疼痛的新型药物治疗方法。小胶质细胞和星形胶质细胞（胶质细胞）的激活在慢性疼痛状态中起着至关重要的作用，包括神经性疼痛，通过慢性诱导释放神经兴奋物质，如促炎细胞因子和趋化因子。这种促炎环境包围着神经元，帮助维持与慢性疼痛状态相关的神经元的过度兴奋状态。最佳的治疗方法是将这些长期激活的神经胶质细胞“重置”到明显的抗炎状态，从而使神经元兴奋恢复到基础水平。这样的药物，如果存在的话，预计会通过消除神经胶质激活提供的疼痛系统的强直性“驱动”来减少神经性疼痛。我们相信我们已经确定了这样的代理人；即腺苷2A （A2A）激动剂。从机制上讲，它们是一种腺苷受体亚型的激动剂。腺苷是一种嘌呤，通过g蛋白偶联腺苷受体A1、A2A、A2B和A3四种亚型发挥作用。腺苷2A受体存在于人体大多数组织中，包括脊髓神经元、小胶质细胞、星形胶质细胞、内皮细胞和少突胶质细胞。A2A受体亚型的选择性激活具有免疫抑制作用，减少促炎细胞因子，增加强效抗炎细胞因子白介素-10 （IL-10）。此外，A2A受体的激活降低了初级感觉神经元中NMDA的激活。使用慢性收缩损伤（CCI）模型的初步数据支持单次鞘内注射A2A激动剂可产生至少数周的显著持久神经性疼痛逆转。为了充分了解A2A激动剂对慢性疼痛的影响，我们建议：1)彻底表征单次注射与多次注射后已确定的神经性疼痛的逆转，以确定是否对激动剂的疼痛抑制作用产生耐受性；并且，2)开始描述参与激动剂疼痛抑制的细胞类型。虽然作用机制很可能包括神经元-胶质细胞的相互作用，但鉴于胶质细胞在疼痛发展和维持中的已知作用，我们的重点将放在胶质细胞的变化上，并在时间和资金允许的情况下同时评估神经元的变化。此外，我们将评估A2A激动剂的持续作用是A2A腺苷受体特异性的，还是通过其他腺苷受体调节腺苷的调节会产生同样的效果。

DESCRIPTION (provided by applicant): : Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain Project Summary/Abstract This application addresses broad Challenge Area (15) Translational Science & specific Challenge Topic 15- NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. Neuropathic pain remains intractable despite treatment with currently available therapeutic agents. Therefore, it is necessary to identify novel pharmacotherapeutics that can effectively attenuate neuropathic pain. Activation of microglia and astrocytes (glial cells) plays a crucial role in chronic pain states, including neuropathic pain, by chronically inducing the release of neuroexcitatory substances such as pro-inflammatory cytokines and chemokines. This pro-inflammatory milieu surrounds neurons, helping to maintain the hyperexcitable state of neurons associated with chronic pain states. An optimal therapeutic would "reset" these chronically activated glial cells to an overtly anti-inflammatory state, thus returning the neuronal excitation to basal levels. Such a drug, were it to exist, would be predicted to reduce neuropathic pain by removing the tonic "drive" to the pain system provided by glial activation. We believe that we have identified such agents; namely, adenosine 2A (A2A) agonists. Mechanistically, these are agonists at one adenosine receptor subtype. Adenosine is a purine that exerts its effects via four subtypes of G-protein coupled adenosine receptors (A1, A2A, A2B and A3). Adenosine 2A receptors are found on most tissues in the body including spinal cord neurons, microglia, astrocytes, endothelial cells and oligodendrocytes. The selective activation of the A2A receptor subtype is immunosuppressive, decreasing pro-inflammatory cytokines and increasing the powerful anti-inflammatory cytokine, interleukin-10 (IL-10). In addition, activation of A2A receptors reduces NMDA activation in primary sensory neurons. Preliminary data, using the chronic constriction injury (CCI) model, support that a single intrathecal injection of A2A agonists produces a remarkably enduring reversal of neuropathic pain of at least several weeks. In order to fully understand the impact of A2A agonists on chronic pain conditions, we are proposing to 1) thoroughly characterize the reversal in established neuropathic pain following a single versus multiple injections to ascertain if tolerance to the agonist's pain suppressive effects develops; and, 2) begin to characterize the cell types involved in the agonist's pain suppression. While the mechanism of action most likely includes a neuron-glia interaction, given the known role of glia in pain development and maintenance, our focus will be on glial changes, with neuronal changes assessed concurrently as time and funds allow. In addition, we will assess whether the persistent effect of the A2A agonist is specific to the A2A adenosine receptor or if modulating adenosine regulation via other adenosine receptors will produce the same effect. PUBLIC HEALTH RELEVANCE: NINDS Proposal: Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain Project Narrative This proposal builds from our discovery that a single intrathecal administration of adenosine 2A (A2A) agonists produces a remarkably enduring reversal of neuropathic pain of at least several weeks, with evidence to date suggestive that such drugs may "reset" chronically activated spinal glial cells to an overtly anti-inflammatory state that suppresses pain. This project is aimed at providing the "proof-of-concept" for using A2A agonists as a new therapeutic approach for chronic pain.