Dual-Acting Peripherally Restricted Delta/Kappa Opioid (CAV1001) Produces Antinociception in Animal Models of Sub-Acute and Chronic Pain.
Dual-Acting Peripherally Restricted Delta/Kappa Opioid (CAV1001) Produces Antinociception in Animal Models of Sub-Acute and Chronic Pain.
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DOI：
10.2147/jpr.s262303
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发表时间：
2020
影响因子：
2.7
通讯作者：
Hartrick A
中科院分区：
文献类型：
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作者：
Hartrick CT;Poulin D;Molenaar R;Hartrick A
开发高效的Mu-阿片类镇痛剂替代品是尚未得到满足的迫切医疗和公共卫生需求。在炎症存在的情况下，作用于外周感觉神经元的β-阿片激动剂和kappa类阿片激动剂都介导了镇痛作用。双作用、外周受限的kappa/Delta阿片激动剂CAV1001在四种啮齿动物疼痛模型上进行了测试。实验1-小鼠福尔马林试验。福尔马林注射后30min检测CAV1001或ICI204448 3个剂量(1~10 mg/kg)。对自发伤害性反应进行录像。实验2-完全弗氏佐剂(CFA)诱导的关节炎。将CFA注入大鼠踝关节。测量关节受压阈值(JCT)。CAV1001与塞来昔布进行比较。实验3-大鼠脊髓神经结扎(SNL)。测定足爪压缩阈值(PCT)。CAV1001与加巴喷丁进行比较。实验4-MMRT-1大鼠胫骨种植骨癌。对负重进行评估。将CAV1001与吗啡进行比较。在福尔马林模型的第二阶段，CAV1001(1 mg/kg)显著减少疼痛行为，其程度与外周受限的kappa-阿片激动剂ICI204448(10 mg/kg)相当。CAV1001(10 mg/kg)有效地消除了与第二时相有关的疼痛行为。在CFA诱导的关节炎模型中，CAV1001 1 mg/kg在2小时时显著增加JCT，与对照组塞来昔布相似；CAV1001(10 mg/kg)在1小时时有效。在SNL模型中，对照药加巴喷丁和CAV1001(5 mg/kg)均在2小时显著降低PCT，但在4小时，CAV1001阈值提高到基线水平。与植入MMRT-1后的基线相比，CAV100110 10 mg/kg在给药后4小时显著改善了体重。CAV1001在几种不同的临床前疼痛模型中显示了有效性。在这些啮齿动物疼痛模型中，CAV1001疗效的时间和剂量依赖的差异与潜在的炎症程度平行。
The development of highly efficacious alternatives to mu-opioid analgesics represents an urgent unmet medical and public health need. In the presence of inflammation both delta- and kappa-opioid agonists, acting on peripheral sensory neurons, mediate analgesia. The dual-acting, peripherally restricted kappa/delta-opioid agonist, CAV1001, was tested in four rodent pain models. Experiment 1 – Formalin testing in mice. Three doses (1–10 mg/kg) of CAV1001 or ICI204448 at 30 minutes were tested after formalin injection. Spontaneous nocifensive responses were video recorded. Experiment 2 – Complete Freund’s Adjuvant (CFA)-induced arthritis. CFA was injected into the ankle joint of rats. Joint compression thresholds (JCT) were measured. CAV1001 was compared to celecoxib. Experiment 3 – Spinal nerve ligation (SNL) in rats. Paw compression thresholds (PCT) were measured. CAV1001 was compared to gabapentin. Experiment 4 – MMRT-1 bone cancer implantation into the rat tibia. Weight-bearing was assessed. CAV1001 was compared to morphine. In Phase 2 of the formalin model, CAV1001 (1 mg/kg) significantly reduced pain behaviors to a degree comparable to the peripherally restricted kappa-opioid agonist, ICI204448 (10 mg/kg). CAV1001 (10 mg/kg) effectively eliminated pain behaviors associated with phase 2. In the CFA-induced arthritis model, a significant increase in JCTs, similar to the comparator celecoxib, was observed with CAV1001 at 1 mg/kg at 2 hours; CAV1001 (10 mg/kg) was effective at 1 hour. In the SNL model, both the comparator gabapentin and CAV1001 (5 mg/kg) significantly reduced PCT at 2 hours, but at 4 hours, the CAV1001 thresholds improved to baseline. CAV1001 10 mg/kg significantly improved weight bearing at 4-hour post-dosing compared to baseline following MMRT-1 implantation. CAV1001 demonstrated efficacy in several different preclinical pain models. Time- and dose-dependent differences in the efficacy of CAV1001 amongst these rodent pain models parallel the degree of underlying inflammation.