Dehkordi Ozra, Lin Stephen, Mohamud Safia, Millis Richard M, Wang Paul C
Department of Neurology, Howard University Hospital, Washington, D.C. 20060, United States.
Department of Radiology, Howard University Hospital, Washington, D.C. 20060, United States.
Curr Res Physiol. 2025 May 20;8:100147. doi: 10.1016/j.crphys.2025.100147. eCollection 2025.
Respiratory depression is the leading cause of death in opioid overdose and is closely associated with the development of tolerance following repeated morphine use. However, the neurochemical adaptations in brainstem regions that regulate breathing, particularly under chronic opioid exposure, remain poorly understood. G-protein-gated inwardly rectifying potassium (GIRK) channels, especially the GIRK2 subunit, are expressed in rhythm-generating neurons of the pre-Bötzinger complex and have been implicated in opioid-induced respiratory depression. Nonetheless, their specific role in morphine-induced neurochemical changes is not yet fully defined. In this study, proton magnetic resonance spectroscopy (H MRS) was used in mice to assess morphine-induced metabolite changes in ventral brainstem regions encompassing the pre-Bötzinger complex. Wild-type mice were compared with GIRK2 heterozygous (GIRK2/) mutants. Baseline levels of several metabolites including glutamate (Glu), myo-inositol (Ins), N-acetylaspartate plus N-acetylaspartylglutamate (NAA + NAAG), and glutamate plus glutamine (Glu + Gln) differed significantly between GIRK2/ and wild-type mice. Despite these baseline differences, many of morphine's effects on metabolite levels were similar in the wild-type and GIRK2/ mice. Morphine increased phosphocreatine (PCr) in both genotypes, while total creatine (Cr + PCr) decreased only in the wild-type mice. Glutamine levels increased significantly in both groups. Notably, NAA decreased in wild-type but increased in GIRK2/ mice, whereas NAA + NAAG decreased in both. These findings demonstrate that chronic morphine exposure induces substantial neurochemical changes in brainstem respiratory centers. Although the GIRK2/ mutation altered some of the metabolite responses, it does not fully block morphine's effects, highlighting the complexity of opioid-induced adaptations in the respiratory control networks.
呼吸抑制是阿片类药物过量致死的主要原因，且与反复使用吗啡后耐受性的形成密切相关。然而，对于调节呼吸的脑干区域，尤其是在长期阿片类药物暴露情况下的神经化学适应性变化，我们仍知之甚少。G蛋白门控内向整流钾通道（GIRK），特别是GIRK2亚基，在前包钦格复合体的节律性产生神经元中表达，并与阿片类药物诱导的呼吸抑制有关。尽管如此，它们在吗啡诱导的神经化学变化中的具体作用尚未完全明确。在本研究中，我们利用质子磁共振波谱（H MRS）在小鼠中评估吗啡诱导的、包含前包钦格复合体的腹侧脑干区域代谢物变化。将野生型小鼠与GIRK2杂合（GIRK2+/−）突变体进行比较。包括谷氨酸（Glu）、肌醇（Ins）、N-乙酰天门冬氨酸加N-乙酰天门冬氨酰谷氨酸（NAA + NAAG）以及谷氨酸加谷氨酰胺（Glu + Gln）在内的几种代谢物的基线水平在GIRK2+/−小鼠和野生型小鼠之间存在显著差异。尽管存在这些基线差异，但吗啡对代谢物水平的许多影响在野生型和GIRK2+/−小鼠中是相似的。吗啡使两种基因型中的磷酸肌酸（PCr）增加，而总肌酸（Cr + PCr）仅在野生型小鼠中降低。两组中的谷氨酰胺水平均显著升高。值得注意的是，野生型小鼠中的NAA降低，而GIRK2+/−小鼠中的NAA升高，而两者中的NAA + NAAG均降低。这些发现表明，长期吗啡暴露会在脑干呼吸中枢诱导大量神经化学变化。尽管GIRK2+/−突变改变了一些代谢物反应，但它并未完全阻断吗啡的作用，这凸显了阿片类药物诱导的呼吸控制网络适应性变化的复杂性。
