Discriminative Stimulative effects of Opioid Withdrawal

 说明(申请人提供)：阿片受体激动剂仍然是治疗中重度疼痛的首选药物，但其使用受到耐受性、依赖性、滥用和呼吸抑制等不良反应的限制。最近过量服药和死亡人数的增加加剧了人们对阿片类药物进一步限制其合法医疗用途的担忧。越来越多的证据表明，通过将阿片类药物与另一种药物联合使用，可以增加阿片类药物的治疗窗口，这样较小剂量的阿片类药物(与另一种药物联合使用)就能产生预期的治疗效果。与阿片类药物一样，大麻素受体激动剂具有抗伤害性作用，用于治疗疼痛；然而，由于包括滥用在内的不良反应，以及单独使用时在非常有限的条件下有效，它们的使用受到限制。越来越多的证据表明，阿片类药物/大麻类药物组合治疗疼痛可能非常有效和安全。例如，我们的研究表明，在猴子中，在不增加阿片类药物产生增强或歧视性刺激效应的效力的剂量下，阿片类药物产生抗伤害感受的效力显著增加。这些结果是在急性给药后获得的，尽管疼痛的治疗通常需要反复药物治疗。尽管阿片类药物/大麻类药物组合具有潜在的临床效用，但对每日重复给药的后果知之甚少；拟议的研究将我们的初步发现扩展到重复给药，以更接近疼痛患者的治疗模式。这些研究检验了这样一种假设，即通过将小剂量的阿片类药物与大麻素结合起来，可以减少或避免限制其临床使用的阿片类药物的不良影响。目的1比较阿片受体激动剂芬太尼与阿片受体激动剂CP55,940联合应用的长期疗效，以验证阿片/大麻联合应用减少或预防阿片耐受和身体依赖的假说。目的2使用猴子在芬太尼单独或芬太尼和CP55940的组合之间进行选择的程序，评估阿片类药物/大麻类药物组合的滥用潜力(积极强化效应)。目的3研究阿片/大麻联合用药的其他潜在不良反应(镇静、复杂作业能力受损和呼吸抑制)以及芬太尼和CP55940之间可能的药代动力学相互作用。这些研究将描述阿片/大麻素组合的特点，这些组合通过选择性地减少治疗效果所需的阿片类药物剂量，从而增加阿片类药物的治疗窗口，从而减少并可能避免目前限制阿片类药物合法医疗使用的不良反应的发生。使用一种对人类高度可翻译的物种和程序，这些研究将为这种创新的疼痛治疗方法提供概念验证。

 DESCRIPTION (provided by applicant): Opioid receptor agonists remain the drugs of choice to treat moderate to severe pain, but their use is limited by adverse effects including tolerance, dependence, abuse, and respiratory depression. A recent increase in overdoses and deaths is fueling concerns about opioids that further limit their legitimate medical use. A growing body of evidence indicates that the therapeutic window of an opioid can be increased by combining it with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Like opioids, cannabinoid receptor agonists have antinociceptive effects and are used to treat pain; however, their use is limited because of adverse effects, including abuse, and because they are effective under a very limited range of conditions when administered alone. Converging lines of evidence indicate that opioid/cannabinoid combinations might be very effective and safe for treating pain. For example, our studies show that in monkeys the potency of opioids to produce antinociception is increased significantly by cannabinoids at doses that do not increase the potency of opioids for producing reinforcing or discriminative stimulus effects. Those results were obtained following acute administration of drugs, although treatment of pain often requires repeated drug treatment. Despite the potential clinical utility of opioid/cannabinoid combinations, little is known about th consequences of repeated daily administration of combinations; the proposed studies extend our initial findings to repeated drug administration to more closely model treatment in pain patients. These studies test the hypothesis that the adverse effects of opioids, that limit their clinical use, are reduced or avoided by combining small doses of an opioid with a cannabinoid. Aim 1 compares the long- term effects of daily dosing with the high efficacy opioid receptor agonist fentanyl administered alone and in combination with the high efficacy cannabinoid receptor agonist CP55,940 to test the hypothesis that administration of an opioid/cannabinoid combination reduces or prevents the development of opioid tolerance and physical dependence. Aim 2 assesses the abuse potential (positive reinforcing effects) of opioid/cannabinoid combinations using a choice procedure in which monkeys choose between fentanyl alone and a combination of fentanyl and CP55,940. Aim 3 characterizes other potential adverse effects of opioid/cannabinoid combinations (sedation, impaired complex task performance, and respiratory depression) and possible pharmacokinetic interactions between fentanyl and CP55,940. These studies will characterize opioid/cannabinoid combinations that increase the therapeutic window of opioids by selectively decreasing the dose of opioid necessary for therapeutic effects, thereby reducing and possibly avoiding the occurrence of adverse effects that currently limit the legitimate medical use of opioids. 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.