Modulation of local adenosine signaling to attenuate fracture pain

调节局部腺苷信号传导以减轻骨折疼痛

• 批准号: 10614931
• 负责人: Shyni Varghese
• 金额: $ 48.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614931
• 关键词: 3-Dimensional; Acceleration; Acids; Acute Pain; Address; Adenosine; Adenosine A1 Receptor; Affect; Afferent Neurons; Agonist; Analgesics; Animals; Appearance; Attenuated; Behavior; Biocompatible Materials; Bone Injury; Bone callus; Brain-Derived Neurotrophic Factor; Buprenorphine; Caring; Central Nervous System; Clinical; Cyclic AMP; Data; Dependence; Development; Dinoprostone; Dissociation; Dose; Economic Burden; Environment; Esthesia; Facial Expression; Fracture; Gel; Goals; Harvest; Hyaluronic Acid; In Vitro; Injectable; Injury; Ion Channel; Light; Locomotion; Matrix Metalloproteinases; Mechanics; Mediating; Medical; Membrane Potentials; Microfluidic Microchips; Microfluidics; Mus; Nerve; Neurons; Neuropeptides; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Orthopedic Surgery; Orthopedics; Osteogenesis; Pain; Pain management; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Prevalence; Production; Purinergic P1 Receptors; Receptor Signaling; Regulation; Role; Sensory Receptors; Series; Signal Transduction; Site; Small Interfering RNA; Stains; Stimulus; TRPV1 gene; Testing; Therapeutic; Therapeutic Agents; Tibial Fractures; Tissues; Trauma; Weight-Bearing state; Work; addiction liability; antagonist; behavior test; bone fracture repair; chronic pain; conditional knockout; crosslink; experimental study; extracellular; gait examination; healing; improved; in vivo; knock-down; neurite growth; neurotrophic factor; novel therapeutic intervention; novel therapeutics; pain reduction; pain relief; pain sensitivity; receptor; receptor expression; scaffold; side effect; skeletal; skeletal tissue; small molecule; success; therapeutically effective; tibia; transcriptome sequencing; transcriptomics

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.

摘要