Analgesic effect of neohesperidin is mediated by TRPV1 antagonism

Abstract

Context: Transient receptor potential vanilloid type 1 (TRPV1) is a non-specific cation channel. It is one of the most important targets in pain research. Aims: To evaluate new TRPV1 antagonists without altering body temperature. Methods: Docking simulation was performed, and one of the candidate compounds, neohesperidin, was tested using thermal and chemical pain models in BALB/c mice. Rectal body temperature was measured using a temperature meter with a thermocouple probe detector, and the capsaicin-evoked calcium response was determined in dorsal root ganglia (DRG) neurons. Results: Docking resulted in the identification of 30 compounds able to interact with the essential amino acids required for the antagonistic activity of TRPV1. Neohesperidin was chosen for further investigations because of its good binding energy (-6.63 kcal/mol) and because its TRPV1 antagonistic activity was not tested before. This study reported for the first time that neohesperidin exerted analgesic activity through TRPV1 antagonism without altering body temperature. Its activity was comparable to the known TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). In the writhing test, acetic acid-induced abdominal cramps decreased by 66% using 30 mg/kg of neohesperidin. All tested doses of neohesperidin significantly decreased paw-licking time in the capsaicin-induced paw-licking test. A significant increase in the latency time in hot plate and tail flick tests was observed using 30 and 60 mg/kg of neohesperidin. In DRG neurons, neohesperidin reduced capsaicin-evoked calcium responses. Conclusions: Neohesperidin exerts a significant analgesic activity without altering body temperature, which could be due, at least partially, to its antagonistic activity against TRPV1.