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

项目摘要 使用高度成瘾的MU阿片受体(MOR)靶向止痛药治疗急性疼痛，如 羟考酮、氢可酮和氢吗啡酮是目前美国阿片类药物过量的主要原因。 由于这些阿片类止痛药固有的快感诱导(“奖励”)作用，可能会导致严重的流行病。 激活kappa阿片受体(KOR)的化合物，当与MOR靶向阿片类药物联合给药时 止痛药，不仅可以降低这些回报性，还可以增强其止痛性 属性。然而，由于耐受性差，传统的(“公正的”)KOR激活剂在临床上失败了。 使用无偏倚的KOR激动剂后产生的许多负面副作用被认为与 参与G蛋白非依赖的信号通路。因此，有人提出，较新的G蛋白- 有偏见的KOR激动剂可能会保留其治疗益处，而不会通过减少 它们通过这些不依赖于G蛋白的途径发出信号的程度。因此，我的长期目标是 提供适当水平的临床前验证，以支持偏重于G蛋白的KOR的未来临床试验 作为一种抗成瘾/节省剂量的辅助剂的激动剂纳呋芬将与MOR靶向一起使用 阿片类止痛药。鉴于纳呋芬目前在日本的使用情况，它立即成为一种切实的佐剂候选药物 用于尿毒症瘙痒及其十年的安全性和耐受性历史。通过这种方式，成功的临床前测试 使用纳呋芬作为佐剂将实质性地推进一种新的(且迅速易于处理的)战略，以减少 用常规阿片类止痛药治疗急性疼痛的成瘾倾向。在短期内，我会 进行关键的基于老鼠的效应、副作用和体内信号研究，将呋喃西林与临床上的 相关的MOR靶向止痛药吗啡、羟考酮、氢可酮和氢吗啡酮，以支持 这个长期目标。目的1是通过小鼠行为测试来确定纳呋芬的治疗效果。 作为一种佐剂，在不影响其成瘾性的情况下降低莫尔靶向止痛药的成瘾潜力 抗伤害作用。目标2是确定与联合给药有关的抗治疗风险 纳呋芬与吗啡类阿片类止痛药通过小鼠行为测试了解已知方 无偏见的KOR激动剂的效果(即烦躁不安、抑郁、焦虑和精神分裂)。临床前 证明呋喃呋喃是阿片类止痛药的减瘾添加剂的证据应该会导致 未来这种药物组合在急性疼痛适应症中的人体试验。在这种情况下，我的建议是响应性的 NIDA特别关注NOT-19-048“预防药物使用、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”.