Subanalgesic morphine doses augment fentanyl analgesia by interacting with delta opioid receptors in male rats.
Subanalgesic morphine doses augment fentanyl analgesia by interacting with delta opioid receptors in male rats.
复制标题
亚镇痛吗啡剂量通过与雄性大鼠的 δ 阿片受体相互作用来增强芬太尼的镇痛作用。
DOI：
10.1002/jnr.24944
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发表时间：
2022
影响因子：
4.2
通讯作者：
Gutstein,HowardB
中科院分区：
文献类型：
--
作者：
Barker,KatherineE;Lecznar,AlynnJ;Schumacher,JillM;Morris,JeffreyS;Gutstein,HowardB
阿片类药物常用于治疗术后和创伤后疼痛;然而，其治疗效果受到不良和危及生命的副作用的限制。长期以来，研究人员一直试图开发阿片类药物联合给药疗法来增强镇痛，但阿片类药物镇痛的复杂性和我们对机制的不完全理解使这成为一项艰巨的任务。我们发现，皮下给药后，亚镇痛吗啡剂量（100 ng/kg-10 µg/kg）可增强芬太尼（20 µg/kg）对雄性大鼠的急性镇痛作用。此外，对未处理大鼠脊髓膜给予等效药物比例诱导G蛋白活化增加两倍。GTP水解速率保持不变。我们证明了这些行为和生化效应是由δ阿片受体（DOP）介导的。亚镇痛剂量的DOP选择性激动剂SNC 80也增强了芬太尼的急性镇痛作用。此外，DOP拮抗剂纳曲吲哚与芬太尼-吗啡和芬太尼-SNC 80组合的共同给药阻止了镇痛和G蛋白活化的增强。μ阿片受体（MOP）拮抗剂cyprodime没有阻止增强。芬太尼，亚镇痛吗啡，或这种组合治疗的大鼠胶状质的共聚焦显微镜显示，MOP内化的变化并不占增强效应。总之，这些研究结果表明，增强芬太尼镇痛亚镇痛吗啡介导的G蛋白活化增加MOPs和DOP之间的协同作用或异源二聚化。这一发现具有重要的治疗意义，因为它提出了开发DOP选择性配体的策略，可以提高临床使用的MOP药物的治疗指数。
Opioids are commonly used for the treatment of postoperative and post‐traumatic pain; however, their therapeutic effectiveness is limited by undesirable and life‐threatening side effects. Researchers have long attempted to develop opioid co‐administration therapies that enhance analgesia, but the complexity of opioid analgesia and our incomplete mechanistic understanding has made this a daunting task. We discovered that subanalgesic morphine doses (100 ng/kg–10 µg/kg) augmented the acute analgesic effect of fentanyl (20 µg/kg) following subcutaneous drug co‐administration to male rats. In addition, administration of equivalent drug ratios to naïve rat spinal cord membranes induced a twofold increase in G protein activation. The rate of GTP hydrolysis remained unchanged. We demonstrated that these behavioral and biochemical effects were mediated by the delta opioid receptor (DOP). Subanalgesic doses of the DOP‐selective agonist SNC80 also augmented the acute analgesic effect of fentanyl. Furthermore, co‐administration of the DOP antagonist naltrindole with both fentanyl‐morphine and fentanyl‐SNC80 combinations prevented augmentation of both analgesia and G protein activation. The mu opioid receptor (MOP) antagonist cyprodime did not block augmentation. Confocal microscopy of the substantia gelatinosa of rats treated with fentanyl, subanalgesic morphine, or this combination showed that changes in MOP internalization did not account for augmentation effects. Together, these findings suggest that augmentation of fentanyl analgesia by subanalgesic morphine is mediated by increased G protein activation resulting from a synergistic interaction between or heterodimerization of MOPs and DOPs. This finding is of great therapeutic significance because it suggests a strategy for the development of DOP‐selective ligands that can enhance the therapeutic index of clinically used MOP drugs.