Characterization of A-425619 at native TRPV1 receptors: A comparison between dorsal root ganglia and trigeminal ganglia

Abstract

1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea (A-425619), a novel, potent, and selective transient receptor potential type V1 (TRPV1) antagonist, attenuates pain associated with inflammation and tissue injury in rats. The purpose of this study was to extend the in vitro characterization of A-425619 to native TRPV1 receptors and to compare the pharmacological properties of TRPV1 receptors in the dorsal root ganglion with trigeminal ganglion neurons. A robust increase in intracellular Ca 2+ was elicited by a variety of TRPV1 agonists with similar rank order of potency between both cultures: resiniferatoxin > tinyatoxin > capsaicin > N-arachidonoyl-dopamine (NADA). A-425619 blocked the 500 nM capsaicin response in both dorsal root ganglion with trigeminal ganglion cultures with IC 50 values of 78 nM and 115 nM, respectively, whereas capsazepine was significantly less potent (dorsal root ganglia: IC 50 = 2.63 μM; trigeminal ganglia: IC 50 = 6.31 μM). Furthermore, A-425619 was more potent in blocking the 3 μM NADA-evoked response in both dorsal root ganglia (IC 50 = 36 nM) and trigeminal ganglia (IC 50 = 37 nM) than capsazepine (dorsal root ganglia, IC 50 = 741 nM; trigeminal ganglia, IC 50 = 708 nM). Electrophysiology studies showed that 100 nM A-425619 completely inhibited TRPV1-mediated acid activated currents in dorsal root ganglia and trigeminal ganglia neurons. In addition, A-425619 blocked capsaicin- and NADA-evoked calcitonin gene-related peptide (CGRP) release in both cultures more effectively than capsazepine. These data show that A-425619 is a potent TRPV1 antagonist at the native TRPV1 receptors, and suggest that the pharmacological profile for TRPV1 receptors on dorsal root ganglia and trigeminal ganglia is very similar.