Jin Daozhong, Chen Hong, Zhou Meng-Hua, Huang Yuying, Chen Shao-Rui, Pan Hui-Lin
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Signal. 2025 Sep 2;18(902):eadu8839. doi: 10.1126/scisignal.adu8839.
Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein Gα in this paradox. Pharmacological inhibition of Gα in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gα coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of Gα in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of Gα signaling enhanced morphine's analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gα signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.
阿片类药物通过激活μ-阿片受体（MORs）来缓解疼痛，μ-阿片受体可抑制痛觉神经元（伤害感受器）与脊髓之间的信号传递。然而，长期使用阿片类药物可能会反常地导致疼痛敏感性增加（痛觉过敏）和镇痛效果降低（耐受性），部分原因是脊髓中初级感觉神经元中央终末处的NMDA型谷氨酸受体（NMDARs）被激活。在此，我们确定了G蛋白Gα在这一矛盾现象中的关键作用。对大鼠的Gα进行药理学抑制可逆转吗啡诱导的NMDAR磷酸化增加、突触转运以及感觉神经元终末处的活性，并减少吗啡诱导的对脊髓背角神经元的兴奋性伤害性输入。吗啡增强了Gα与脊髓中代谢型谷氨酸受体5（mGluR5）二聚体的特异性偶联。此外，在小鼠背根神经节神经元中靶向敲低Gα可使NMDAR相关变化恢复正常，并防止由MOR激活触发的NMDAR介导的突触增强。此外，对Gα信号进行药理学或基因干扰可增强吗啡的镇痛作用，同时减少痛觉过敏和耐受性。这些发现表明，Gα信号通过促进MOR-mGluR5相互作用，导致阿片类药物诱导的伤害感受器中央终末处的NMDAR活性亢进。针对这一途径可能会提高基于阿片类药物的疼痛管理的安全性和有效性。
