Behavioral effects of NMDA antagonist/opioid agonist combinations

描述（由申请人提供）：处方药的误用和滥用，特别是止痛药，已升级为美国第二大最常见的药物滥用类别。虽然适当使用处方止痛剂成瘾的风险很低，但其广泛供应导致滥用问题日益严重，处方止痛剂的非医疗使用/滥用增加了一倍。降低NMDA受体活性的药物已被证明可以阻断疼痛通路中的致敏作用，而疼痛通路是从急性疼痛进展为慢性疼痛的基础。此外，许多增强阿片类药物的镇痛作用，并防止对阿片类药物的耐受性和依赖性的发展。不幸的是，NMDA受体拮抗剂作为药物的开发已经受到限制使用的副作用的阻碍，所述副作用包括镇静/运动性共济失调和滥用倾向，如原型NMDA拮抗剂氯胺酮所例示的。拟议研究的目标是使用滥用相关药物作用和镇痛作用的临床前模型来研究选择NMDA受体调节剂与阿片类药物的组合，这是一种临床相关的疼痛管理方法，以确定它们是否可以提供相对于氯胺酮的改善的治疗指数。在Aim 1中，我们将研究在恒河猴自我给药程序中，选择的NMDA药物是否表现出相对于氯胺酮的奖励作用减弱。此外，我们将评估羟考酮和纳布啡单独使用以及与感兴趣的NMDA药物联合使用的强化特性，以确定它们是否会改变阿片类药物的滥用潜力。目的2将使用食物强化的操作性反应评估NMDA药物单独和与阿片类药物组合的镇静作用。在目的3中，我们将使用辣椒素诱导的恒河猴热异常性疼痛模型评估NMDA药物单独和与羟考酮或纳布啡组合的治疗功效。目的是通过比较目的1和2中确定的产生氯胺酮样副作用的倾向与在临床相关镇痛模型中产生治疗效果的倾向，鉴定相对于氯胺酮具有改善的治疗比的化合物。在 目的4：研究最佳NMDA类药物对羟考酮和纳布啡产生的身体依赖性的抑制作用。这些方法并不新颖，但同时使用这些方法评估新型NMDA/阿片类药物联合给药提供了一种评价这些联合治疗临床潜力的独特方法。使用非人灵长类动物可确保对药物的药效学和药代动力学相互作用进行遗传学上最适当的评价，从而增强结果对人类的可转化性。确定安全有效的新方法来提供镇痛将显着改善疼痛的医疗管理，并可能导致减少处方药滥用和成瘾的转移和风险。

DESCRIPTION (provided by applicant): The misuse and abuse of prescription drugs, particularly pain relievers, has escalated to become the second most common category of substance abuse in the US. While risk of addiction to prescription analgesics when properly used is low, their widespread availability has led to a growing abuse problem, and nonmedical use/abuse of prescription analgesics has doubled. Drugs that decrease NMDA receptor activity have been shown to block sensitization development in pain pathways that underlie progression from acute to chronic pain conditions. Additionally many enhance the analgesic effects of opioids and prevent the development of tolerance and dependence to opioids. Unfortunately, development of NMDA receptor antagonists as medications has been hindered by the production of use-limiting side effects including sedation/motor ataxia and abuse liability as exemplified by the prototypic NMDA antagonist ketamine. The goal of the proposed research is to use preclinical models of abuse-related drug effects and analgesic effects to investigate select NMDA receptor modulators in combination with opioid medications, a clinically relevant pain management approach, to determine if they can provide an improved therapeutic index relative to ketamine. In Aim1 we will investigate whether select NMDA drugs demonstrate diminished rewarding effects relative to ketamine in a self-administration procedure in rhesus monkeys. Additionally, we will assess the reinforcing properties of oxycodone and nalbuphine alone and in combination with the NMDA drugs of interest to determine if they will alter the abuse potential of the opioids. Aim 2 will assess the sedative effects of the NMDA drugs alone and in combination with the opioids using food-reinforced operant responding. In Aim 3, we will assess the therapeutic efficacy of the NMDA drugs alone and in combination with oxycodone or nalbuphine using, a capsaicin-induced model of thermal allodynia in rhesus monkeys. The goal is to identify the compound(s) with improved therapeutic ratios relative to ketamine by comparison of their propensity for production of ketamine- like side effects determined in Aims 1 and 2 to that for production of therapeutic effects in a clinically relevant model of analgesia. In Aim 4 we will investigate the ability of the optimal NMDA drugs to attenuate the development of physical dependence produced by oxycodone and nalbuphine. The individual methodologies are not new, however the use of them in parallel to assess novel NMDA/opioid drug combinations provides a unique approach to evaluating the clinical potential of these combination therapies. The use of nonhuman primates ensures the most phylogenetically appropriate evaluation of the pharmacodynamic and pharmacokinetic interactions of the drugs which enhances the translatability of the results to humans. Identification of safe and effective novel approaches to providing analgesia will significantly improve the medical management of pain and may result in decreased diversion and risk for prescription drug abuse and addiction.