Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
Genome, Cell, and Developmental Biology Program, Indiana University, Bloomington, Indiana, USA.
Cannabis Cannabinoid Res. 2021 Oct;6(5):389-400. doi: 10.1089/can.2020.0059. Epub 2020 Oct 21.
Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore, an urgent need to identify safe and effective therapeutics that can attenuate fentanyl-induced respiratory depression. Identification of effective alternate analgesic strategies that lessen the respiratory depression associated with narcotics would also help improve current strategies for pain management. Our laboratory recently reported that the G protein-biased CB cannabinoid receptor agonist LY2828360 suppressed chemotherapy-induced neuropathic nociception and attenuated both morphine tolerance and physical dependence in paclitaxel-treated mice. However, the impact of LY2828360 on other undesirable side effects of opioids, such as opioid-induced respiratory depression, remains unknown. We used whole-body plethysmography to assess the impact of the CB cannabinoid agonist LY2828360 on fentanyl-induced respiratory depression using wild-type (WT) and CB knockout (CBKO) mice. Fentanyl reduced minute ventilation and respiratory frequency without altering tidal volume in both WT and CBKO mice. In WT mice, the high dose of fentanyl (0.2 mg/kg intraperitoneal [i.p.]) produced a greater suppression of respiratory parameters compared with the low dose of fentanyl (0.1 mg/kg i.p.). Coadministration of a behaviorally active dose of LY2828360 (3 mg/kg i.p.) with fentanyl (0.2 mg/kg i.p.) attenuated fentanyl-induced respiratory depression in WT mice. Notably, LY2828360 (3 mg/kg i.p.) did not attenuate fentanyl-induced respiratory depression in CBKO mice, consistent with mediation by CB receptors. Moreover, LY2828360 (3 mg/kg i.p.) alone lacked intrinsic effects on respiratory parameters in either WT or CBKO mice. The combination of a CB agonist with fentanyl may represent a safer adjunctive therapeutic strategy compared with a narcotic analgesic alone by attenuating the development of opioid-induced respiratory depression. Moreover, the CB agonist, administered alone, did not alter respiration. Our findings suggest that the CB cannabinoid agonist LY2828360 may provide CB-mediated protection against fentanyl-induced respiratory depression, a detrimental and unwanted side effect of opioid use and abuse.
与阿片类药物流行相关的过量致死可归因于药物引起的呼吸抑制。就非法阿片类药物滥用而言，芬太尼是导致过量死亡人数最多的合成阿片类药物。因此，迫切需要确定安全有效的治疗方法来减轻芬太尼引起的呼吸抑制。确定减轻与麻醉品相关的呼吸抑制的有效替代镇痛策略也将有助于改善当前的疼痛管理策略。我们的实验室最近报告称，G 蛋白偏向 CB 大麻素受体激动剂 LY2828360 抑制了化疗引起的神经性疼痛，并减轻了紫杉醇治疗小鼠的吗啡耐受和身体依赖。然而，LY2828360 对其他阿片类药物的不良副作用（如阿片类药物引起的呼吸抑制）的影响仍不清楚。我们使用全身 plethysmography 评估 CB 大麻素激动剂 LY2828360 对芬太尼引起的呼吸抑制的影响，使用野生型（WT）和 CB 敲除（CBKO）小鼠。芬太尼降低了分钟通气量和呼吸频率，而潮气量在 WT 和 CBKO 小鼠中没有改变。在 WT 小鼠中，高剂量的芬太尼（0.2mg/kg 腹腔内[ip.]) 与低剂量的芬太尼（0.1mg/kg ip.]) 相比，对呼吸参数的抑制作用更大。行为活性剂量的 LY2828360（3mg/kg ip.]) 与芬太尼（0.2mg/kg ip.]) 联合给药可减轻 WT 小鼠中芬太尼引起的呼吸抑制。值得注意的是，LY2828360（3mg/kg ip.]) 不能减轻 CBKO 小鼠中芬太尼引起的呼吸抑制，这与 CB 受体介导一致。此外，LY2828360（3mg/kg ip.]) 本身对 WT 或 CBKO 小鼠的呼吸参数均无内在作用。与单独使用麻醉性镇痛药相比，将 CB 激动剂与芬太尼联合使用可能代表一种更安全的辅助治疗策略，可减轻阿片类药物引起的呼吸抑制的发展。此外，单独给予 CB 激动剂不会改变呼吸。我们的研究结果表明，CB 大麻素激动剂 LY2828360 可能通过提供 CB 介导的保护来对抗芬太尼引起的呼吸抑制，这是阿片类药物使用和滥用的一种有害和不期望的副作用。
