Modulation of local adenosine signaling to attenuate fracture pain

摘要 骨科骨折引起的疼痛的管理仍然是一个挑战，作为常见的镇痛药物 如非甾体抗炎药（NSAID）和阿片类药物，要么干扰愈合，要么具有 不必要的副作用，如依赖性。考虑到骨科手术引起的疼痛的普遍性 和骨折，迫切需要开发可以减轻疼痛，同时 促进骨折愈合。这促使我们研究腺苷（ADO）作为治疗药物的潜在用途。 用于管理骨折疼痛的药剂。ADO是一种天然存在的小分子，在受伤时释放， 对周围神经和中枢神经有镇痛作用。我们和其他人已经表明，细胞外ADO是 一种促进骨形成和骨折愈合的有效骨合成代谢剂。骨合成代谢功能 ADO沿着的镇痛功能使其成为治疗骨折疼痛的理想分子。的首要目标 该提案旨在评估ADO在骨折损伤疼痛管理中的应用， 基本了解ADO如何减轻骨折疼痛，并开发新的临床可行的治疗方法 战略布局为此，该提案的目标1将开发和表征一种可注射的生物材料，用于局部 将ADO递送至骨折部位，并确定对骨折愈合的剂量依赖性作用。以确定 生物材料辅助的ADO局部给药是否在骨折损伤后提供镇痛作用， 目标2将通过开发DRG芯片进行疼痛行为测试、组织分析、体外分析 平台和RNA测序。目的3将检验ADO介导的骨折疼痛缓解 涉及A1受体（A1R），通过使用感觉神经元中A1R的条件性敲除的动物， 阐明了它对离子通道的调节作用。这项提案的完成将建立一种新的治疗分子 用于骨折创伤的护理，并可能改变骨损伤的治疗方式。我们的广泛影响 使用ADO局部给药的研究可以扩展到各种类型的急性和 起源于外周或中枢神经系统的慢性疼痛。

ABSTRACT Management of pain arising from orthopedic fractures remains a challenge as common analgesic medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and opiates either interfere with healing or possess unwanted side effects such as dependence. Given the prevalence of pain associated with orthopedic surgeries and bone fractures, there is an urgent need to develop therapeutic strategies that can mitigate pain while promoting fracture healing. This motivated us to study the potential use of adenosine (ADO) as a therapeutic agent for managing fracture pain. ADO is a naturally occurring small molecule that is released upon injury and elicits analgesic effects in peripheral and central nerves. We and others have shown that extracellular ADO is an effective osteoanabolic agent promoting bone formation and fracture healing. The osteoanabolic function of ADO along with the analgesic function makes it an ideal molecule to treat fracture pain. The overarching goal of the proposal is to assess the use of ADO for the management of pain in fracture injuries by advancing the fundamental understanding of how ADO mitigates fracture pain and developing new clinically viable therapeutic strategies. Towards this, Aim 1 of the proposal will develop and characterize an injectable biomaterial for local delivery of ADO to the fracture site, and determine the dose-dependent effect on fracture healing. To determine whether biomaterial-assisted local delivery of ADO provides analgesic effects following fracture injury, studies in Aim 2 will perform behavioral tests for pain, tissue analyses, in vitro analyses by developing DRG-on-Chip platforms, and RNA sequencing. Aim 3 will test the hypothesis that ADO-mediated fracture pain mitigation involves A1 receptors (A1Rs) by using animals with conditional knockout of A1R in sensory neurons, and elucidates its regulation of ion channels. Completion of this proposal will establish a new therapeutic molecule for the care of fracture trauma, and potentially change how bone injuries are treated. The broad impact of our studies using localized delivery of ADO could be extended to the management of various types of acute and chronic pain that originate in the peripheral or central nervous system.