Oxytocin-mediated modulation of peripheral mechanical sensibility after injury

催产素介导的损伤后外周机械敏感性调节

• 批准号: 10332263
• 负责人: Mario Danilo Boada
• 金额: $ 33.3万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10332263
• 关键词: Acute; Acute Pain; Address; Affect; Aftercare; Animal Behavior; Animals; Attention; Automobile Driving; Behavior; Behavioral; Chronic; Data; Development; Disease; Dose; Drug Kinetics; Exposure to; Fiber; Goals; Hour; Human; Hypersensitivity; Infusion procedures; Injury; Intravenous infusion procedures; Joints; Ligation; Maintenance; Mechanics; Mechanoreceptors; Mediating; Modification; Nerve Block; Nervous system structure; Neuraxis; Neurobiology; Neurons; Neuropathy; Nociception; Nociceptors; Operative Surgical Procedures; Oxytocin; Pain; Pain management; Patients; Peripheral; Peripheral Nerves; Persistent pain; Pharmacodynamics; Pharmacology; Phenotype; Physiological; Placebos; Plasma; Postoperative Pain; Process; Property; Prophylactic treatment; Publishing; Rattus; Recovery; Research; Resolution; Role; Sensory; Site; Speed; Spinal Cord; Spinal nerve structure; Stimulus; Tactile; Testing; Time; Trauma; Traumatic injury; Work; base; desensitization; electrical property; injured; mechanical stimulus; nerve damage; nerve injury; neurophysiology; neurotransmission; pain chronification; pain reduction; pain relief; pharmacodynamic model; receptive field; response; response to injury; sensory input; translational study; treatment optimization

SUMMARY. The current proposal addresses fundamental neurophysiological questions related to oxytocin (OXT) pharmacology and pain neurobiology in normal and nerve injury settings. We aim to define (a) the OXT PK/PD relationships on fast-conducting afferents (A-fibers), both tactile (LTMRs: low threshold mechanoreceptors) and nociceptive (AHTMRs: A-fiber high threshold mechanoreceptors), (b) to study the effects of L5 SNL at the peak of maximal sensitization (week 2) on injured (L5) and uninjured (L4) afferents and the OXT-mediated modulation of these sensitization process and (c) to correlate the OXT-induced modulation of sensibility (L4) and excitability (L5) with the animal behavior (normal or abnormal) after recovery (weeks 8-12). Our working hypothesis has two parts: 1) that A-fibers response to injury (LTMR: desensitization and AHTMR: sensitization) is critical for the development of a peripheral mediated neuropathic state and 2) that OXT can resolve this state and modulate the recovery by rescuing these afferents from they abnormal excitability. We anticipate that this research will contribute to understanding the physiological effects of OXT, how much of overall central effects can be explained by the OXT peripheral modulation (interaction with Project 2, Dr. Martin), and how these effects can be optimized for the treatment of pain in human patients (interaction with Project 3, Dr. Eisenach).

摘要 目前的建议解决基本的神经生理学问题有关催产素（OXT） 药理学和疼痛神经生物学在正常和神经损伤设置。我们的目的是定义（a）OXT PK/PD 与快速传导传入（A纤维）的关系，包括触觉（LTMR：低阈值机械感受器）和 伤害感受性（AHTMR：A-纤维高阈值机械感受器），（B）研究L5 SNL在峰值时的作用 损伤（L5）和未损伤（L4）传入神经的最大致敏（第2周）和OXT介导的调制 以及（c）将OXT诱导的敏感性（L4）和兴奋性的调节关联起来 (L5)恢复后（8-12周）动物行为（正常或异常）。 我们的工作假设有两个部分：1）A纤维对损伤的反应（LTMR：脱敏和AHTMR： 致敏）对于外周介导的神经病性状态的发展是关键的，以及2）OXT可以 解决这种状态，并通过将这些传入神经从异常兴奋性中拯救出来来调节恢复。我们 预计这项研究将有助于了解OXT的生理效应，总体 中枢效应可以通过OXT外周调节（与项目2的相互作用，Martin博士）来解释， 如何优化这些效果以治疗人类患者的疼痛（与项目3的互动， Eisenach）。