Neuroprotective Role of PGC-1α Against Oxidative Stress and Mitochondrial Dysfunction in Chronic Pain...

Chronic pain imposes a significant burden on global healthcare systems, and existing pharmacological interventions often provide inadequate pain management. Long-term opioid therapy for chronic pain has contributed to the ongoing global opioid crisis, and its utilization is restricted by severe adverse effects including tolerance, addiction risks, and fatal respiratory suppression. Available evidence highlights the role of oxidative damage and impaired mitochondrial function in chronic pain across musculoskeletal, neuropathic, cancer, and opioid-induced pain models. However, recent preclinical studies have shown that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) has the potential to provide effective chronic pain management and to suppress adverse outcomes of chronic opioid therapy. PGC-1α acts by coordinating mitochondrial renewal, redox balance, and neuroinflammation within neural pathways. Its suppression drives mitochondrial dysfunction and pain chronification. Therefore, advancing research into the role of PGC-1α in chronic pain management could uncover effective therapeutic interventions with safer clinical outcomes. However, comprehensive reviews that integrate mechanistic evidence on PGC-1α from multiple chronic pain models-with drug-repurposing implications-remain limited in the literature. This narrative review synthesizes evidence on PGC-1α involvement in chronic pain and examines potential therapeutic interventions through the modulation of PGC-1α as a novel neuroprotective target. Activation of PGC-1α has been shown to attenuate mitochondrial abnormalities and pain hypersensitivity in several preclinical models. Natural compounds, repurposed drugs, and synthetic small-molecule compounds targeting PGC-1α have shown promise as bioactive agents for modulating mitochondrial dysfunction, oxidative stress, and neuroinflammation. However, most available data are preclinical and highlight a translational gap between experimental findings and clinical application across various nociceptive models. Therefore, additional investigation is required to clarify tissue-specific pathways, optimize PGC-1α pharmacological activators, and establish the safety and translational relevance of modulating PGC-1α in chronic pain.