Opioid-Sparing and Pain-Reducing Properties of Syntocinon: A Dose-Effect Determination

Syntocinon 的阿片类药物节省和减轻疼痛特性：剂量效应测定

• 批准号: 10543556
• 负责人: Meredith Berry
• 金额: $ 17.69万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543556
• 关键词: Absence of pain sensation; Acute Pain; Address; Affect; Analgesics; Animal Model; Animals; Area; Biochemistry; Brain; Brain region; Buprenorphine; Cardiovascular system; Corpus striatum structure; Dose; Double-Blind Method; Drug Prescriptions; Formulation; Goals; Grant; Health; Heroin; Hour; Human; Impairment; Individual; Inflammation; Intervention; Intravenous; Laboratory Study; Link; Literature; Manuscripts; Measures; Mechanics; Mediator; Mentors; Methadone; Morbidity - disease rate; Morphine; Motivation; Mus; Neurobiology; Neurons; Neuropeptides; Opiate Addiction; Opioid; Opioid replacement therapy; Oral; Oxycodone; Oxytocin; Pain; Pain Disorder; Pain Measurement; Pain management; Pathway interactions; Percocet; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebo Effect; Placebos; Prefrontal Cortex; Property; Public Health; Randomized; Rattus; Recreation; Reducing Agents; Regulation; Research; Rest; Rewards; Scientific Advances and Accomplishments; Self Administration; Sensory; Source; Standardization; Stimulus; Stress; Structure; Supervision; System; Techniques; Testing; Translations; Writing; abuse liability; addiction; analog; antinociception; behavioral economics; behavioral pharmacology; brain pathway; brain volume; career; chronic pain; conditioned place preference; hedonic; inter-individual variation; mortality; multidisciplinary; multimodal neuroimaging; multimodality; neurobiological mechanism; neuroimaging; novel; novel therapeutics; opioid abuse; opioid epidemic; opioid injection; opioid misuse; opioid mortality; opioid overdose; opioid sparing; opioid use disorder; opioid user; overdose death; pain chronification; pain model; pain reduction; pain sensitivity; pre-clinical; preservation; prevent; respiratory; response; skills; substance use treatment

ABSTRACT Opioid misuse is a major source of morbidity and mortality in the U.S. and represents a pressing public health crisis. Opioid-related overdose deaths have more than quadrupled since 2002. Oxycodone (in Percocet™ and Oxycontin™) is reliably among the medications commonly prescribed for pain, but is also widely abused and involved in overdose deaths. Despite its abuse potential, oxycodone is effective for reducing acute pain. There is an urgent need for interventions that preserve the analgesic properties of oxycodone while curtailing its abuse potential. A promising adjunctive treatment option for pain management, that could simultaneously reduce the abuse liability of opioids, is syntocinon (the intranasal formulation of the neuropeptide oxytocin). Syntocinon may reduce opioid abuse potential, and simultaneously has analgesic properties. Animal models have shown that oxytocin decreases opioid intravenous self- administration and reverses oxycodone conditioned place preference. Rat models of pain show that oxytocin enhances anti-nociception (blocking of painful stimuli), and in humans, syntocinon administration decreases pain sensitivity experimentally. Further, evidence in animals and humans support the shared brain structure and function changes associated with both addiction and chronic pain, which may be modulated by oxytocin administration. Based on the existing literature, we propose that syntocinon will significantly reduce abuse liability of opioids and reduce experimental pain via its effects on brain structure, function and biochemistry. Thirty healthy recreational opioid users will self-administer 48 IUs of intranasal syntocinon (or placebo) shortly after oral oxycodone (0, 2.5, 5.0 mg) in a double-blind, randomized, placebo-controlled, within- subjects laboratory study. Subject-rated abuse liability and cardiovascular and respiratory responses will be assessed before and repeatedly for 5 hours following drug administration. Pain and neurobiological measures will also be collected, including a standardized experimental pain battery (i.e., quantitative sensory testing) and a multi-modal neuroimaging battery (i.e., brain structure, function, and biochemistry). This study has tremendous potential for public health impact in examining intranasal oxytocin as a promising agent for reducing opioid addictive potential, while effectively reducing pain, which could substantially advance the field of pharmacotherapy and carve out a novel treatment option. This study will also advance scientific understanding of neurobiological mechanisms underlying the link between abuse potential and pain. This research will also facilitate the PI’s career goals and path to independence by developing expertise in 1) multi-modal assessments of pain; 2) neuroimaging techniques as they relate to addiction and pain; 3) deepen current expertise in addiction and human behavioral pharmacology in the context of opioid administration and translation; 4) grant and manuscript writing skills; and 5) enhance management and supervision skills. This multidisciplinary team is uniquely suited to mentor the PI in these areas and address the proposed aims.

摘要 阿片类药物滥用是美国发病率和死亡率的主要来源，并代表了一种紧迫的公众 健康危机。自2002年以来，与阿片类药物相关的过量死亡人数增加了四倍多。羟考酮(在 ™和奥施康定(™)是常用的止痛药中可靠的一种，但也被广泛使用 被滥用并参与吸毒过量死亡。尽管羟考酮有可能被滥用，但它对减少急性 疼痛。迫切需要干预措施，以保持羟考酮的止痛特性，同时 减少了它的滥用潜力。这是一种有希望的疼痛管理辅助治疗选择，可以 同时减少阿片类药物的滥用责任，是辛西酮(鼻腔内制剂) 神经肽催产素)。Syntocinon可以减少阿片类药物滥用的可能性，同时具有 止痛特性。动物模型表明，催产素减少阿片类药物静脉注射的自身 给药并逆转羟考酮条件性位置偏爱。大鼠疼痛模型显示催产素 增强抗伤害性(阻断疼痛刺激)，在人类中，给予辛西林可减轻疼痛 实验上的敏感性。此外，在动物和人类身上的证据支持共同的大脑结构和 与成瘾和慢性疼痛相关的功能变化，这可能是由催产素调节的 行政管理。在现有文献的基础上，我们提出辛西酮将显著减少滥用。 阿片类药物的易感性及通过其对脑结构、功能和功能的影响减轻实验性疼痛 生物化学。30名健康的娱乐类阿片使用者将自我给药48国际单位的辛西酮(或 安慰剂)口服羟考酮(0，2.5，5.0毫克)后不久，双盲，随机，安慰剂对照，在- 受试者实验室研究。受试者评定的滥用倾向以及心血管和呼吸系统反应 在给药前和给药后重复5h进行评估。疼痛和神经生物学测量 还将收集，包括标准化的实验性疼痛电池(即定量感觉测试)和 多模式神经成像电池(即大脑结构、功能和生物化学)。这项研究有 检查鼻内催产素作为一种有希望的药物对公共卫生产生巨大影响的潜力 减少阿片成瘾潜力，同时有效减轻疼痛，这可以极大地推动 药物治疗，开辟了一种新的治疗选择。这项研究也将促进科学理解 滥用潜能和疼痛之间潜在联系的神经生物学机制。这项研究还将 通过发展1)多模式评估方面的专业知识，促进PI的职业目标和独立道路 2)与成瘾和疼痛有关的神经成像技术；3)深化目前成瘾方面的专业知识 和人类行为药理学在阿片类药物给药和翻译的背景下；4)赠款和 稿件写作技能；5)提高管理和监督能力。这个多学科团队是 独一无二地适合在这些领域指导PI，并解决拟议的目标。