Dimethyl Fumarate and Cobalt Protoporphyrin IX Inhibit Fibromyalgia-Like Pain by Modulating Region-Specific Redox Pathways

Fibromyalgia is a chronic nociplastic pain disorder characterized by widespread pain and affective disturbances, in which oxidative stress and neuroinflammation are now recognized as central pathogenic mechanisms. However, current therapies provide only limited symptomatic relief. This study compared the therapeutic and molecular effects of dimethyl fumarate (DMF), an activator of nuclear factor erythroid 2-related factor 2 (NRF2), and cobalt protoporphyrin IX (CoPP), an inducer of heme oxygenase-1 (HO-1), in a reserpine-induced mouse model of fibromyalgia-like pain. Male and female C57BL/6J mice received repeated reserpine administration to induce mechanical allodynia, thermal hyperalgesia, cold allodynia, and depressive-like behaviors. Therapeutic efficacy was evaluated by behavioral testing and molecular analyses of the periaqueductal gray (PAG), anterior cingulate cortex (ACC), and spinal cord (SC). DMF produced a faster antinociceptive response than CoPP, although both compounds ultimately reversed nociceptive hypersensitivity and depressive-like behaviors in male and female mice. These behavioral alterations were associated with increased NLRP3 expression and activated AKT signaling, together with region-specific redox dysregulation involving differential regulation of NADPH oxidases and endogenous antioxidant defenses. Both treatments differentially modulated region-specific redox alterations, enhanced selected antioxidant defenses, and attenuated inflammatory and nociception-related signaling. These findings identify region-specific redox dysregulation as a prominent feature of fibromyalgia-like pathology, providing new mechanistic insight into the molecular basis of nociplastic pain. Collectively, these results demonstrate that DMF and CoPP treatments remodel region-specific redox networks while inhibiting both sensory and affective manifestations of fibromyalgia-like pain, supporting endogenous antioxidant pathways as promising mechanism-based therapeutic targets for fibromyalgia.