Abstract

The transient receptor potential vanilloid 1 receptor (TRPV1) is expressed predominantly in a subset of primary afferent nociceptors. Due to its specific anatomical location and its pivotal role as a molecular integrator for noxious thermal and chemical stimuli, there is considerable interest to develop TRPV1 antagonists for the treatment of pain. Recently, N-(4-chlorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl) thiourea (IBTU) was synthesized, and it was found in vitro to be a high-affinity competitive antagonist of cytoplasmic, but not intracellular, TRPV1. In this study, we examined the in vivo antinociceptive activity of IBTU in several acute and inflammatory pain models in mice. Our emphasis was on nociceptive pathways that are likely mediated by TRPV1, including capsaicin-, noxious heat-, and proton (including inflammation)-induced nociception tests. Capsazepine was used as a positive control in these experiments. IBTU dose-dependently blocked the capsaicin-induced nociception, confirming its antagonism at TRPV1 in vivo. By itself, IBTU produced significant antinociception, because it significantly prolonged the tail-flick latency in a dose-dependent manner. IBTU also blocked both early and late phases of the formalin-induced flinching response as well as acetic acid-induced writhing behavior. Moreover, IBTU inhibited the complete Freund's adjuvant-induced persistent hyperalgesia. Taken together, these data demonstrate that IBTU acts as a TRPV1 antagonist in vivo, and they suggest that it may be of therapeutic use for the treatment of pain.