Behavioral effects of NMDA antagonist/opioid agonist combinations

描述(申请人提供)：滥用和滥用处方药，特别是止痛药，已经上升为美国第二常见的药物滥用类别。虽然正确使用处方止痛药成瘾的风险很低，但它们的广泛使用导致了日益严重的滥用问题，非医疗使用/滥用处方止痛药的情况翻了一番。降低NMDA受体活性的药物已被证明可以阻止疼痛通路中敏感化的发展，这是从急性疼痛到慢性疼痛的基础。此外，许多药物可增强阿片类药物的止痛效果，防止对阿片类药物的耐受性和依赖性的形成。不幸的是，NMDA受体拮抗剂作为药物的开发一直受到使用限制副作用的产生的阻碍，包括镇静/运动性共济失调和滥用倾向，典型的NMDA拮抗剂氯胺酮就是例证。这项拟议的研究的目标是使用与滥用相关的药物效应和止痛效应的临床前模型来研究选择的NMDA受体调节剂与阿片类药物的结合，以确定它们是否可以提供相对于氯胺酮的改善治疗指数。在Aim1中，我们将调查在恒河猴的自我给药过程中，与氯胺酮相关的精选NMDA药物是否显示出减弱的回报效应。此外，我们将单独评估羟考酮和纳布芬的增强性能，并与感兴趣的NMDA药物联合使用，以确定它们是否会改变阿片类药物的滥用潜力。目标2将评估NMDA药物单独和与阿片类药物联合使用食物增强操作剂反应的镇静效果。在目标3中，我们将评估NMDA药物单独以及与羟考酮或纳布芬联合使用的疗效，这是一种辣椒素诱导的恒河猴热过敏模型。我们的目标是通过比较目标1和目标2中确定的产生氯胺酮样副作用的倾向与在临床相关的镇痛模型中产生疗效的倾向来确定相对于氯胺酮具有更高治疗比率的化合物(S)。在……里面 目的研究优化的NMDA类药物对羟考酮和纳布芬所致的身体依赖的抑制作用。单独的方法并不新鲜，但同时使用它们来评估新的NMDA/阿片类药物组合为评估这些联合疗法的临床潜力提供了一种独特的方法。非人类灵长类动物的使用确保了对药物的药效学和药动学相互作用的最适当的系统发育评估，从而提高了结果对人类的可译性。确定安全和有效的新的止痛方法将大大改善疼痛的医疗管理，并可能导致减少处方药物滥用和成瘾的转用和风险。

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.