Evaluation of drug mixtures for treating pain: behavioral and pharmacological interactions between opioids and serotonin agonists

项目总结 阿片类药物仍然是治疗中重度疼痛的黄金标准，但其使用受到许多限制。 副作用包括耐受性、依赖性、滥用和过量用药。不良影响可以通过以下方式避免 将一种阿片类药物与另一种药物结合，使较小剂量的阿片类药物(与另一种药物联合使用) 产生预期的治疗效果。直接作用的5-HT2受体激动剂在 与阿片类吗啡协同作用产生抗伤害效应，提示存在5-HT2受体 激动剂可以与小剂量的阿片类药物联合治疗疼痛，从而降低与 更大的剂量。然而，人们对5-HT2受体激动剂与其他阿片类药物之间的相互作用知之甚少。 目前还不清楚5-HT2受体激动剂是否会增强其他不良反应，特别是与 滥用或过量服用或改变阿片类药物反复治疗的后果。建议的研究评估 阿片类药物和5-HT2受体激动剂混合物的治疗潜力使用高度可翻译和良好的 已建立的程序来表征抗伤害感受性、呼吸抑制药(过量)、阳性- 药物混合物的强化(滥用)和区别性刺激(主观)效应以及 对阿片类药物产生耐受性和身体依赖的慢性治疗。AIM 1中的研究 表征阿片类药物和5-HT2受体激动剂之间的急性相互作用的抗伤害效应和 研究5-HT2受体亚型的作用。AIM 2中的研究评估了急性呼吸系统- 含阿片类药物和5-阿片类药物的混合物的抑制、正增强和鉴别刺激作用 HT2受体激动剂。Aim 3的研究比较了阿片类药物和5-HT2混合物每日给药的效果 受体激动剂与阿片类药物单独给药的受体激动剂相比，以评估在发育过程中的变化 容忍和身体依赖。这些研究将确定阿片类药物和5-HT2受体的组合 通过减少阿片类药物所需的阿片类药物剂量来增加阿片类药物治疗窗口的激动剂 治疗效果，同时也减少了目前限制合法医疗使用的不良反应 阿片类药物(耐受、依赖、滥用和过量)和5-HT2受体激动剂(主观影响)。vbl.使用 一种对人类高度可翻译的物种和程序，这些研究将为 这一创新的疼痛治疗方法以及靶向5-羟色胺受体用于止痛的有效性评估 药物开发。

PROJECT SUMMARY Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small dose of an opioid to treat pain thereby lowering the risk associated with larger doses. However, little is known about interactions between 5-HT2 receptor agonists and other opioids, and it is unclear whether 5-HT2 receptor agonists enhance other adverse effects, particularly those relating to abuse or overdose or alter the consequences of repeated treatment with an opioid. Proposed studies evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well- established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive- reinforcing (abuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. Studies in Aim 1 characterize acute interactions between opioids and 5-HT2 receptor agonists for antinociceptive effects and examine the contribution of 5-HT2 receptor subtypes. Studies in Aim 2 evaluate the acute respiratory- depressant, positive reinforcing, and discriminative stimulus effects of mixtures containing an opioid and a 5- HT2 receptor agonist. Studies in Aim 3 compare effects of daily dosing with a mixture of an opioid and a 5-HT2 receptor agonist to those of the opioid administered alone in order to evaluate changes in the development of tolerance and physical dependence. These studies will identify combinations of opioids and 5-HT2 receptor agonists that increase the therapeutic window of opioids by decreasing the dose of opioid necessary for therapeutic effects, while also reducing the adverse effects that currently limit the legitimate medical use of opioids (tolerance, dependence, abuse and overdose) and 5-HT2 receptor agonists (subjective effects). Using a species and procedures that are highly translatable to humans, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.