Danaf Jamil, da Silveira Scarpellini Carolina, Montandon Gaspard
St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
Department of Medicine, University of Toronto, Toronto, ON, Canada.
Front Physiol. 2023 Apr 6;14:1043581. doi: 10.3389/fphys.2023.1043581. eCollection 2023.
Opioid medications are the mainstay of pain management but present substantial side-effects such as respiratory depression which can be lethal with overdose. Most opioid drugs, such as fentanyl, act on opioid receptors such as the G-protein-coupled µ-opioid receptors (MOR). G-protein-coupled receptors activate pertussis toxin-sensitive G-proteins to inhibit neuronal activity. Binding of opioid ligands to MOR and subsequent activation G proteins βγ is modulated by regulator of G-protein signaling (RGS). The roles of G-proteins βγ and RGS in MOR-mediated inhibition of the respiratory network are not known. Using rodent models to pharmacologically modulate G-protein signaling, we aim to determine the roles of βγ G-proteins and RGS4. We showed that inhibition of βγ G-proteins using gallein perfused in the brainstem circuits regulating respiratory depression by opioid drugs results in complete reversal of respiratory depression. Blocking of RGS4 using CCG55014 did not change the respiratory depression induced by MOR activation despite co-expression of RGS4 and MORs in the brainstem. Our results suggest that neuronal inhibition by opioid drugs is mediated by G-proteins, but not by RGS4, which supports the concept that βγ G-proteins could be molecular targets to develop opioid overdose antidotes without the risks of re-narcotization often found with highly potent opioid drugs. On the other hand, RGS4 mediates opioid analgesia, but not respiratory depression, and RGS4 may be molecular targets to develop pain therapies without respiratory liability.
阿片类药物是疼痛管理的主要手段，但会产生严重的副作用，如呼吸抑制，过量使用可能会致命。大多数阿片类药物，如芬太尼，作用于阿片受体，如G蛋白偶联的μ-阿片受体（MOR）。G蛋白偶联受体激活对百日咳毒素敏感的G蛋白以抑制神经元活动。阿片配体与MOR的结合以及随后G蛋白βγ的激活受G蛋白信号调节剂（RGS）调节。G蛋白βγ和RGS在MOR介导的呼吸网络抑制中的作用尚不清楚。我们使用啮齿动物模型对G蛋白信号进行药理学调节，旨在确定βγ G蛋白和RGS4的作用。我们发现，通过在调节阿片类药物引起的呼吸抑制的脑干回路中灌注加兰他敏来抑制βγ G蛋白，可导致呼吸抑制完全逆转。尽管RGS4和MOR在脑干中共表达，但使用CCG55014阻断RGS4并没有改变MOR激活所诱导的呼吸抑制。我们的结果表明，阿片类药物引起的神经元抑制是由G蛋白介导的，而不是由RGS4介导的，这支持了βγ G蛋白可能是开发阿片类药物过量解毒剂的分子靶点的概念，而不会有强效阿片类药物常见的再次麻醉风险。另一方面，RGS4介导阿片类镇痛作用，但不介导呼吸抑制，RGS4可能是开发无呼吸副作用的疼痛治疗方法的分子靶点。
