LAUSR

Complex regional pain syndrome type I (CRPS‐I) is a disabling pain condition that typically arises after ischemia/reperfusion injury. Managing its acute and chronic pain remains challenging. The transient receptor potential vanilloid 4 (TRPV4) channel is involved in neuropathic and inflammatory pain, making it a potential target for CRPS‐I treatment. Thus, we evaluate the participation of the TRPV4 channel in nociception and spinal neuroinflammation induced by a preclinical model of CRPS‐I. Male mice (C57BL/6) were used for chronic post‐ischemia pain (CPIP) induction. Mechanical allodynia, thermal hypersensitivity, and rotarod test were performed before (baseline) and post‐induction of CPIP (Days 1, 5, 10, and 15). Open field test was performed on Days 1 and 15, and nest‐building behavior was observed on the 15th–16th day after CPIP induction. The antinociceptive effect of the TRPV4 antagonist HC‐067047 (1 mg/kg, intraperitoneal) was evaluated over 15 days. CPIP‐Veh (vehicle) mice exhibited mechanical allodynia and thermal hypersensitivity. HC‐067047 repeated treatment reduced nociception from day 5 to 15 post‐CPIP induction. In the open field test, CPIP‐Veh mice spent less time in the central zone, a parameter reversed by HC‐067047 treatment. Additionally, nest‐building scores improved with repeated treatment of HC‐067047. Elevated levels of putative endogenous TRPV4 ligands, hydrogen peroxide (H2O2) and nitric oxide (NO), were reduced after HC‐067047 repeated treatment. CPIP‐induced increased gene expression of spinal protease‐activated receptor 2 (Par2, a sensitizer of TRPV4), Trpv4, glial fibrillary acidic protein (Gfap, to evaluate astrocyte activation), and nuclear factor erythroid 2–related factor 2 (Nrf2, a biomarker of antioxidant defense). HC‐067047 repeated treatment attenuated it, except for Trpv4 levels, which remained unaltered. These results suggest that the TRPV4 channel is likely involved in CRPS‐I nociceptive mechanisms in mice.