title: Attenuation of thermal nociception and hyperalgesia by VR1 blockers.
abstract: Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 [N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] and DD191515 [[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain.
authors.affiliation: Centro de Biología Molecular y Celular, Universidad Miguel Hernández, Alicante, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: García-Martinez
authors.forename: Marc
authors.initials: M
authors.lastname: Humet
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: Ana
authors.initials: A
authors.lastname: Gomis
authors.forename: Marco
authors.initials: M
authors.lastname: Caprini
authors.forename: Felix
authors.initials: F
authors.lastname: Viana
authors.forename: Elvira
authors.initials: E
authors.lastname: De La Pena
authors.forename: Francisco
authors.initials: F
authors.lastname: Sanchez-Baeza
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbonell
authors.forename: Carmen
authors.initials: C
authors.lastname: De Felipe
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Paya
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005998:Glycine / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia; D007249:Inflammation / Q000188:drug therapy; D007717:Knee / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009149:Mustard Plant; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D017288:Pain Threshold; D034444:Peptoids; D010936:Plant Extracts / Q000494:pharmacology; D010938:Plant Oils; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D014981:Xenopus
chemical_list: D034444:Peptoids; D010936:Plant Extracts; D010938:Plant Oils; D011955:Receptors, Drug; D011994:Recombinant Proteins; D002211:Capsaicin; D002118:Calcium; D005998:Glycine; C027793:mustard oil