TRPV4 Channel Participates in the Nociception and Spinal Neuroinflammation Involved in a Model of Complex Regional...

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.