title: Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin.
abstract: (1) Stimulation of the vanilloid receptor-1 (TRPV1) results in the activation of nociceptive and neurogenic inflammatory responses. Poor specificity and potency of TRPV1 antagonists has, however, limited the clarification of the physiological role of TRPV1. (2) Recently, iodo-resiniferatoxin (I-RTX) has been reported to bind as a high affinity antagonist at the native and heterologously expressed rat TRPV1. Here we have studied the ability of I-RTX to block a series of TRPV1 mediated nociceptive and neurogenic inflammatory responses in different species (including transfected human TRPV1). (3) We have demonstrated that I-RTX inhibited capsaicin-induced mobilization of intracellular Ca(2+) in rat trigeminal neurons (IC(50) 0.87 nM) and in HEK293 cells transfected with the human TRPV1 (IC(50) 0.071 nM). (4) Furthermore, I-RTX significantly inhibited both capsaicin-induced CGRP release from slices of rat dorsal spinal cord (IC(50) 0.27 nM) and contraction of isolated guinea-pig and rat urinary bladder (pK(B) of 10.68 and 9.63, respectively), whilst I-RTX failed to alter the response to high KCl or SP. (5) Finally, in vivo I-RTX significantly inhibited acetic acid-induced writhing in mice (ED(50) 0.42 micro mol kg(-1)) and plasma extravasation in mouse urinary bladder (ED(50) 0.41 micro mol kg(-1)). (6) In in vitro and in vivo TRPV1 activated responses I-RTX was approximately 3 log units and approximately 20 times more potent than capsazepine, respectively. This high affinity antagonist, I-RTX, may be an important tool for future studies in pain and neurogenic inflammatory models.
authors.affiliation: Department of Experimental & Clinical Medicine, Pharmacology Unit, University of Ferrara, Via Fossato di Mortara 19, 44100 Ferrara, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Rigoni
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
authors.forename: David
authors.initials: D
authors.lastname: Gazzieri
authors.forename: Riccardo
authors.initials: R
authors.lastname: Nadaletto
authors.forename: Michele
authors.initials: M
authors.lastname: Tognetto
authors.forename: Christophe
authors.initials: C
authors.lastname: Creminon
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
authors.forename: Barbara
authors.initials: B
authors.lastname: Campi
authors.forename: Silvia
authors.initials: S
authors.lastname: Amadesi
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Selena
authors.initials: S
authors.lastname: Harrison
mesh_terms: D000818:Animals; D002460:Cell Line; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004224:Diterpenes; D011955:Receptors, Drug; C468130:iodoresiniferatoxin