Novel Heme Oxygenase-1 Inducers Palliate Inflammatory Pain and Emotional Disorders by Regulating NLRP3 Inflammasome and Activating the Antioxidant Pathway

Chronic pain caused by persistent inflammation is common across multiple diseases and has a strong negative impact on society, often accompanied by anxiety and depression. Current therapies are not sufficiently safe and effective. Recent reports show that induction of heme oxygenase-1 (HO-1) produces analgesic effects in osteoarthritis and improves grip strength after sciatic nerve crush. Here, we evaluated three new HO-1 inducers (1m, 1a, 1b) and dimethyl fumarate (DMF) for treating persistent inflammatory pain induced by complete Freund’s adjuvant (CFA) and the associated functional deficits and emotional symptoms. We also assessed their modulation of inflammatory and antioxidant pathways. Repeated oral treatment for four days with 1m, 1a, 1b, or DMF inhibited inflammatory pain, reversed grip strength deficits, and normalized anxiety- and depressive-like behaviors, with 1m being the most effective. These treatments suppressed up-regulation of the NLRP3 inflammasome and activated expression of Nrf2, HO-1, and superoxide dismutase-1 (SOD-1) in the paw and/or amygdala, revealing anti-inflammatory and antioxidant actions during inflammatory pain. Results support 1m, 1a, 1b, and DMF—particularly 1m—as promising therapies for inflammatory pain and associated functional disabilities and emotional disorders.