Role of GIRK2 channels in morphine-induced metabolite changes in the rostral ventromedial medulla

The rostral ventromedial medulla (RVM) is a brainstem structure that integrates descending modulatory signaling and contains neurons highly responsive to opioid receptor activation. Despite the well-established effects of opioids in the RVM, the neurochemical adaptations following sustained morphine exposure remain poorly understood. In particular, the contribution of G-protein–coupled inwardly rectifying potassium type 2 (GIRK2) channels, key mediators of opioid receptor–dependent antinociception has not been fully characterized. We hypothesized that GIRK2 channels are essential for morphine-induced metabolic alterations in the RVM. In vivo proton nuclear magnetic resonance spectroscopy ( 1 H NMR) was used to examine metabolite responses to prolonged morphine exposure. Metabolite profiles were compared between wild-type and GIRK2 heterozygous mutant (GIRK2 + / − ) mice before and after four days of subcutaneous implantation with placebo or morphine pellets. In wild-type mice, morphine exposure significantly increased levels of phosphocreatine, total creatine, glutamine, glutathione, taurine, and glycerophosphocholine plus phosphocholine (GPC + PCh), while decreasing N -acetylaspartate (NAA). These changes suggest enhanced energy storage, activation of antioxidant pathways, increased membrane turnover, and alterations in neuronal integrity and excitatory neurotransmission. In contrast, GIRK2 + / − mice exhibited attenuated or opposite responses to morphine, characterized by elevated glutamate and reductions in glutamine, GPC + PCh, and total creatine, with no change in NAA. These differential responses indicate that GIRK2 channels influence neurochemical adaptations to morphine in the RVM. These findings identify the GIRK2 channel as an important modulator of morphine-induced metabolic changes in the RVM. The observed neurochemical alterations likely reflect adaptive responses to sustained opioid exposure. • Morphine reduces energy metabolism and enhances antioxidant defenses in the RVM of wild-type mice. • Morphine disrupts the glutamate–glutamine (Glu + Gln) cycle in the RVM of wild-type mice • The GIRK2+/− mutation substantially modifies morphine-induced metabolite changes in the RVM • GIRK2 channel activity is required for the full expression of morphine-induced metabolite changes