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

脊髓腺苷调节剂：在神经性疼痛中持久的抗炎作用项目概述/摘要本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题15- NS-103神经疾病中新治疗方法的“概念验证”的证明。尽管使用目前可用的治疗剂进行治疗，但神经性疼痛仍然是顽固性的。因此，有必要确定新的药物治疗，可以有效地减轻神经病理性疼痛。小胶质细胞和星形胶质细胞（胶质细胞）的活化通过慢性诱导神经兴奋性物质（如促炎细胞因子和趋化因子）的释放在慢性疼痛状态（包括神经性疼痛）中起关键作用。这种促炎环境包围着神经元，有助于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慢性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。这种药物，如果存在的话，将被预测通过消除由神经胶质激活提供的对疼痛系统的紧张性“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商，即腺苷2A（A2 A）激动剂。从机制上讲，这些是一种腺苷受体亚型的激动剂。腺苷是一种嘌呤，通过四种G蛋白偶联腺苷受体亚型（A1，A2 A，A2 B和A3）发挥作用。腺苷2A受体存在于身体的大多数组织上，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。A2 A受体亚型的选择性激活是免疫抑制性的，减少促炎细胞因子并增加强效抗炎细胞因子白细胞介素-10（IL-10）。此外，A2 A受体的激活减少初级感觉神经元中的NMDA激活。使用慢性压迫性损伤（CCI）模型的初步数据支持单次鞘内注射A2 A激动剂产生至少数周的神经性疼痛的显著持久逆转。为了充分理解A2 A激动剂对慢性疼痛病症的影响，我们提议1）在单次注射与多次注射之后彻底表征已建立的神经性疼痛的逆转，以确定是否产生对激动剂的疼痛抑制作用的耐受性;和2）开始表征参与激动剂的疼痛抑制的细胞类型。虽然作用机制最有可能包括神经元-胶质细胞相互作用，但鉴于胶质细胞在疼痛发展和维持中的已知作用，我们的重点将是胶质细胞的变化，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A2 A激动剂的持续作用是否对A2 A腺苷受体特异，或者通过其他腺苷受体调节腺苷调节是否会产生相同的作用。 公共卫生相关性：NINDS提案：脊髓腺苷调节剂：在神经性疼痛中的持久抗炎作用项目叙述该提议基于我们的发现，即腺苷2A（A2 A）激动剂的单次鞘内给药产生至少数周的神经性疼痛的显著持久逆转，迄今为止的证据表明，这种药物可以将慢性激活的脊髓神经胶质细胞“重置”为抑制疼痛的明显抗炎状态。该项目旨在为使用A2 A激动剂作为慢性疼痛的新治疗方法提供“概念验证”。

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.