Therapeutic Potential of Kappa Opioid/Cannabinoid Mixtures for Treating Pain

项目摘要/摘要j. 处方类阿片(Mu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反应(如滥用、呼吸抑制)已有充分记录，而且显著 公共卫生问题。MU阿片类药物是所有处方药中滥用最广泛的， 吸毒过量已经达到了流行的程度。因此，迫切需要更有效的疼痛治疗方法。 更少的有害影响。Kappa阿片受体激动剂不会产生呼吸抑制 很可能被滥用；然而，由于对人类的不良影响，kappa阿片类药物的临床使用已被排除， 如烦躁不安、幻觉和利尿。如果这些集中调节的不利影响能够避免，那么 Kappa阿片类药物可能是治疗疼痛的有希望的靶点，而不是具有较高疗效的Mu阿片类药物 有滥用和过量用药的风险。我们的实验室表明，通过将kappa阿片类药物与一种非阿片类药物相结合 也产生抗伤害作用(例如，大麻素受体激动剂)，混合物中每种药物的剂量较小 以相加的方式产生抗伤害作用。如果小剂量的副作用不明显，那么 Kappa阿片类药物与大麻类药物联合使用可能具有治疗疼痛的潜力。这个 Kappa阿片/大麻素混合物对慢性炎症的治疗潜力可能最大 疼痛胜过其他类型的疼痛。拟议的研究将检验卡帕阿片类药物/大麻类药物的假设 合剂进一步增强慢性炎症大鼠的抗伤害性反应而不是不良反应 Kappa和大麻素受体功能增强，介导外周和脊髓的抗伤害性感受。 目的1表征kappa阿片/大麻素混合物的抗伤害性作用，以检验以下假设 混合物中剂量较小的药物具有比添加剂更强的抗伤害作用。AIM 2用途 量化kappa阿片/大麻混合物不良影响的操作员选择程序以测试 认为一种混合物在炎症大鼠体内效力降低的假说。目标3比较kappa阿片类药物 以及大麻素受体在炎症和非炎症大鼠中的功能。这些研究探索了一种新的和 治疗疼痛的创新方法(kappa阿片/大麻混合物)，目前没有滥用的风险 限制了Mu阿片类药物的临床使用。此外，这笔赠款将支持一项博士后培训计划 申请者要发展独特的研究轨迹，并过渡到独立调查人员的职业生涯。

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.