Therapeutic Potential of Kappa Opioid/Cannabinoid Mixtures for Treating Pain

Kappa 阿片类药物/大麻素混合物治疗疼痛的治疗潜力

• 批准号: 9329184
• 负责人: Vanessa Minervini
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329184
• 关键词: Acute Pain; Adverse effects; Afferent Neurons; Agonist; Area; Attenuated; Behavioral; Binding; Cannabinoids; Chronic; Chronic inflammatory pain; Clinical; Competence; Diuresis; Diuretics; Dose; Epidemic; Female; Freund' s Adjuvant; GTP-Binding Proteins; Grant; Guanosine Triphosphate; Hallucinations; Human; Individual; Inflammation; Infusion procedures; Injection of therapeutic agent; Laboratories; Measures; Mechanics; Mediating; Medical; Messenger RNA; Modeling; Molecular; Opioid; Opioid Receptor; Output; Overdose; Oxycodone; Pain; Pain management; Peripheral; Pharmaceutical Preparations; Pre-Clinical Model; Procedures; Property; Provider; Psychology; Public Health; Rattus; Research; Research Personnel; Rewards; Risk; Sampling; Spinal; Spinal Cord; Spinal Ganglia; Stimulus; System; Techniques; Testing; Therapeutic; Tissues; Training; Urine; Ventilatory Depression; Visit; Withdrawal; afferent nerve; behavioral pharmacology; cannabinoid receptor; career; chronic pain; dysphoria; effective therapy; endogenous opioids; high risk; inflammatory pain; innovation; kappa opioid receptors; male; mu opioid receptors; novel; novel strategies; post-doctoral training; prescription opioid; prevent; protein activation; public health relevance; receptor; receptor binding; receptor function

Project Summary/Abstract j . Prescription opioids (mu opioid receptor agonists) are the drugs of choice for treating moderate to severe pain, despite well-documented adverse effects of those drugs (e.g., abuse, respiratory depression) and significant public health concerns. Mu opioids are the most widely abused of all prescription medications and fatal overdoses have reached epidemic levels. Thus, there is a dire need for more effective treatments for pain with fewer deleterious effects. Kappa opioid receptor agonists do not produce respiratory depression and are not likely to be abused; however, clinical use of kappa opioids has been precluded by adverse effects in humans, such as dysphoria, hallucinations, and diuresis. If these centrally mediated adverse effects can be avoided, then kappa opioids might be promising targets for treating pain and would be preferred to mu opioids that have a high risk of abuse and overdose. Our laboratory showed that by combining a kappa opioid with a non-opioid drug that also produces antinociception (e.g., a cannabinoid receptor agonist), smaller doses of each drug in a the mixture produce antinociceptive effects in an additive manner. If adverse effects are not apparent at smaller doses, then kappa opioids in combination with cannabinoids could have therapeutic potential for treating pain. The therapeutic potential of kappa opioid/cannabinoid mixtures is perhaps greatest for treating chronic inflammatory pain over other types of pain. The proposed studies will test the hypothesis that a kappa opioid/cannabinoid mixture further enhances antinociceptive but not adverse effects in rats with chronic inflammation due to increased function at kappa and cannabinoid receptors that mediate antinociception peripherally and spinally. Aim 1 characterizes the antinociceptive effects of a kappa opioid/cannabinoid mixture to test the hypothesis that smaller doses of drugs in a mixture have antinociceptive effects that are greater than additive. Aim 2 uses operant choice procedures to quantify adverse effects of a kappa opioid/cannabinoid mixture to test the hypothesis that the potency of a mixture is decreased in rats with inflammation. Aim 3 compares kappa opioid and cannabinoid receptor function from rats with and without inflammation. These studies explore a novel and innovative approach (kappa opioid/cannabinoid mixture) for treating pain without the risk of abuse that currently limits the clinical use of mu opioids. Additionally, this grant will support a postdoctoral training plan for the applicant to develop a unique research trajectory and transition to a career as an independent investigator.

项目概要/摘要j . 处方阿片类药物（μ阿片受体激动剂）是治疗中度至重度疼痛的首选药物， 尽管这些药物的不良作用有充分的证据证明（例如，滥用、呼吸抑制）， 公共健康问题。μ阿片类药物是所有处方药中滥用最广泛的， 吸毒过量已达到流行病的程度。因此，迫切需要更有效的疼痛治疗方法， 更少的有害影响。κ阿片受体激动剂不产生呼吸抑制， 可能被滥用;然而，κ阿片类药物的临床使用已被排除在人类中的不良反应， 例如烦躁、幻觉和多尿。如果这些中枢介导的不良反应可以避免， κ阿片样物质可能是治疗疼痛的有希望的靶点， 滥用和过量的风险。我们的实验室表明，通过将κ阿片类药物与非阿片类药物结合， 也产生抗伤害感受（例如，大麻素受体激动剂），混合物中每种药物的较小剂量 以累加的方式产生抗伤害感受效应。如果在较小剂量下不良反应不明显，则 κ阿片类物质与大麻素的组合可能具有治疗疼痛的治疗潜力。的 κ阿片样物质/大麻素混合物的治疗潜力可能最大， 其他类型的疼痛。拟议中的研究将检验κ阿片类/大麻素 混合物进一步增强了抗伤害感受，但对慢性炎症大鼠没有不良作用， 增加介导外周和脊髓抗伤害感受的κ和大麻素受体的功能。 目的1描述了κ阿片类/大麻素混合物的抗伤害作用，以检验以下假设： 混合物中较小剂量的药物具有比相加更大的抗伤害作用。Aim 2用途 操作性选择程序来量化卡帕阿片类药物/大麻素混合物的不良反应，以测试 假设混合物的效力在有炎症的大鼠中降低。Aim 3比较了κ阿片类药物 和大麻素受体的功能。这些研究探索了一部小说， 用于治疗疼痛而没有滥用风险的创新方法（κ阿片类药物/大麻素混合物）， 限制了μ阿片类药物的临床应用。此外，这笔赠款将支持博士后培训计划， 申请人开发一个独特的研究轨迹和过渡到职业生涯作为一个独立的调查员。