Oxytocin: a pain disease-modifying agent in the nervous system after injury

催产素：神经系统受伤后的疼痛缓解剂

• 批准号: 10609942
• 负责人: James Eisenach
• 金额: $ 174.23万
• 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/10609942
• 关键词: Acute; Acute Pain; Affective; Analgesics; Animals; Anti-Anxiety Agents; Anxiety; Area; Behavior; Behavioral; Blood; Brain; Central Nervous System; Cesarean section; Chronic; Clinical; Clinical Research; Cognitive; Computers; Data; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Economics; Feasibility Studies; Female; Fiber; Formulation; Fright; Functional disorder; Goals; Human; Hypersensitivity; Infusion procedures; Injury; Intramuscular; Knowledge; Literature; Mechanoreceptors; Methods; Modeling; Nature; Nerve Block; Nerve Fibers; Nervous System; Neuropathy; Nociception; Operative Surgical Procedures; Oxytocin; Pain; Pain Research; Patients; Pelvis; Penetration; Peripheral; Peripheral Nerves; Persons; Physical therapy; Physiological; Physiology; Process; Psychophysics; Rattus; Recovery; Reporting; Research; Resolution; Rodent; Role; Sensory; Site; Sleep; Social Behavior; Source; Speed; Sweden; Therapeutic; Time; Translations; Trust; Universities; Woman; addiction; behavior measurement; brain tissue; central sensitization; chronic pain; clinical practice; desensitization; disability; efficacy evaluation; electrical property; improved; in vivo; knee replacement arthroplasty; male; multimodality; neurophysiology; neuroprotection; pain behavior; pain chronification; pain reduction; pharmacodynamic model; pharmacokinetics and pharmacodynamics; postoperative recovery; pre-clinical; prevent; response; sensory stimulus; sex; social; tool; translational approach; translational study; transmission process; verbal; vibration perception

This P01 will address fundamental gaps in knowledge that currently impede translation of findings in the preclinical literature to improved clinical practice regarding the utility of oxytocin as a pain therapeutic and potential disease-modifying agent to prevent the transition from acute to chronic pain. Oxytocin itself is the only clinically available tool for translational studies in many areas – neuroprotection, anxiety, sleep, social behaviors, addiction, and pain. Most rodent and human studies of oxytocin lack strong scientific rigor, with only half of the clinical studies examining pain demonstrating efficacy, and we have minimal ability to understand oxytocin effects within and across species. Since chronic pain is usually reduced acutely by peripheral nerve block, peripheral input is necessary, but most research assumes that input is normal and pain reflects ongoing central sensitization. We and others challenge these ideas, showing that LTMRs are desensitized after injury whereas fast high threshold mechanoreceptors (A-HTMRs) are sensitized and behavioral recovery coincides with return to normal function of both afferent subtypes. Importantly, oxytocin acutely moves LTMR and A-HTMR dysfunction after injury towards normal. Pain resolves quicker in women after cesarean delivery than other pelvic surgeries, and hypersensitivity resolves quicker in rodents when neuropathic injury is performed after delivery, an effect blocked by inhibition of oxytocin action. These data suggest that oxytocin may alter the process of chronic pain development after injury or surgery, and has the potential to be not just an acute analgesic, but a disease-modifying therapeutic. Oxytocin has prosocial, anxiolytic, and trust enhancing effects according to small studies in rodents and humans, but the circuitry and role of these central actions on speeding recovery from pain and disability after injury are unexplored. This P01 will address these gaps and advance the field of pain research through the coordinated interactions between the preclinical and clinical projects across 3 specific areas. The first is extrapolation of the pharmacokinetics of oxytocin across species, such that drug exposure in relevant compartments with time are being studied in a coordinated manner that permits interpretation of physiological or behavioral effects between rats and humans Second is the study of primary sensory afferent physiology across species that determines how oxytocin alters specific nerve fiber types and the key electrical properties related to pain transmission, including multiple modes of nociceptive stimulation and their interaction. Third, we study pain behaviors beyond reflexive responses or verbal report in animals and humans, respectively, which may offer greater translational value. Collectively, the coordinated and synergistic nature of these studies will hopefully provide clarity on the potential of oxytocin to mitigate chronic pain development after injury, and the context within such effects occur.

本P01将解决目前阻碍研究结果翻译的基本知识差距