Pre-clinical assessments of dose-sparing and anti-addictive adjuvants to prevent the future abuse of opioid analgesics

项目摘要 用高度成瘾的μ阿片受体（莫尔）靶向镇痛药物治疗急性疼痛， 羟考酮，氢可酮和氢吗啡酮，极大地促进了目前美国阿片类药物过量 由于这些阿片类镇痛药物固有的欣快感诱导（“奖励”）作用， 当与靶向MOR的阿片样物质共同给药时，激活κ阿片样物质受体（KOR）的化合物 止痛药，不仅可以减少这些奖励性质，但也可以提高他们的止痛 特性.然而，常规的（“无偏的”）KOR激活剂由于耐受性差而在临床上失败。 使用无偏KOR激动剂后的许多负面副作用被认为与 与G蛋白无关的信号通路。因此，有人提出，较新的G蛋白- 偏向性KOR激动剂可以通过减少药物的副作用而保留其治疗益处，而不产生负面副作用。 它们通过这些G蛋白非依赖性途径传递信号的程度。因此，我的长期目标是 提供适当水平的临床前验证，以支持G蛋白偏倚KOR的未来临床试验 激动剂纳呋拉芬作为抗成瘾/剂量节省佐剂与MOR靶向给药 阿片类镇痛药鉴于其目前在日本的使用情况，纳呋萘芬是一种立即可行的候选佐剂 治疗尿毒症性瘙痒及其长达十年的安全性和耐受性。通过这种方式，成功的临床前测试 使用纳呋拉芬作为佐剂将实质性地推进一种新的（快速易处理的）策略， 用常规阿片类镇痛药治疗急性疼痛的成瘾性。在短期内，我会 进行关键的小鼠效应、副作用和体内信号传导研究，将纳呋萘芬与临床 相关的MOR靶向镇痛药物吗啡、羟考酮、氢可酮和氢吗啡酮，以支持 这个长期目标。目的1是通过小鼠行为学试验确定纳呋拉芬的治疗效果 作为一种佐剂，降低MOR靶向镇痛药物的成瘾潜力，而不损害其 抗伤害作用。目的2是确定与以下联合给药相关的抗治疗责任： 纳呋萘芬与MOR靶向阿片类镇痛药物通过小鼠行为试验，在已知方面提供信息 无偏KOR激动剂的作用（即烦躁不安、抑郁、焦虑和拟精神病）。临床前 建立纳呋拉芬作为阿片类镇痛药物的成瘾减少添加剂的证据应导致 这种药物组合在急性疼痛适应症中的未来人体试验。这样，我的建议是有求必应的 NIDA的特别关注通知NOT-19-048“防止药物使用，滥用和成瘾的研究”。

Project Abstract Treating acute pain with highly addictive mu opioid receptor (MOR)-targeting analgesic drugs, such as oxycodone, hydrocodone, and hydromorphone, has contributed greatly to the present American opioid overdose epidemic, owing to the inherent euphoria-inducing (“rewarding”) effects of these opioid analgesic drugs. Compounds that activate the kappa opioid receptor (KOR), when co-administered with MOR-targeting opioid analgesic drugs, can not only reduce these rewarding properties, but can also enhance of their painkilling properties. However, conventional (“unbiased”) KOR activators have failed in the clinic due to poor tolerance. Many of the negative side effects that follow the use of unbiased KOR agonists are thought to be associated with engaging G protein-independent signaling pathways. It has therefore been proposed that newer G protein- biased KOR agonists might retain their therapeutic benefits without creating negative side effects by reducing the extent to which they signal through these G protein-independent pathways. My long-term goal is therefore to provide an appropriate level of pre-clinical validation to support future clinical trials of the G protein-biased KOR agonist nalfurafine as an anti-addictive / dose-sparing adjuvant to be administered alongside MOR-targeting opioid analgesic drugs. Nalfurafine is an immediately tangible adjuvant candidate given its current use in Japan for uremic pruritus and its decade-long history of safety and tolerability. In this way, successful pre-clinical testing of the use of nalfurafine as an adjuvant will materially advance a novel (and quickly tractable) strategy to reduce the addictive liability of treating acute pain with conventional opioid analgesic drugs. In the short-term, I will perform key mouse-based effect, side effect, and in vivo signaling studies, pairing nalfurafine with the clinically relevant MOR-targeting analgesic drugs morphine, oxycodone, hydrocodone, and hydromorphone, to support this long-term goal. Aim 1 is to determine, via mouse behavioral assays, the therapeutic efficacy of nalfurafine as an adjuvant that reduces the addictive potential of MOR-targeting analgesic drugs without compromising their anti-nociceptive effects. Aim 2 is to determine the anti-therapeutic liabilities associated with co-administration of nalfurafine with MOR-targeting opioid analgesic drugs via mouse behavioral assays that inform on known side effects of unbiased KOR agonists (namely dysphoria, depression, anxiety, and psychotomimesis). Pre-clinical evidence establishing nalfurafine as an addiction-reducing additive to opioid analgesic drugs should lead to future human trials of such a drug combination in acute pain indications. In this way, my proposal is responsive to NIDA’s Notice of Special Interest NOT-19-048 “Research to Prevent Drug Use, Misuse and Addiction”.