title: Pharmacologic antagonism of the oral aversive taste-directed response to capsaicin in a mouse brief access taste aversion assay.
abstract: Chemosensory signaling by the tongue is a primary determinant of ingestive behavior and is mediated by specific interactions between tastant molecules and G protein-coupled and ion channel receptors. The functional relationship between tastant and receptor should be amenable to pharmacologic methods and manipulation. We have performed a pharmacologic characterization of the taste-directed licking of mice presented with solutions of capsaicin and other transient receptor potential vanilloid-1 (TRPV1) agonists using a brief access taste aversion assay. Dose-response functions for lick-rate suppression were established for capsaicin (EC(50) = 0.5 microM), piperine (EC(50) = 2 muM), and resiniferatoxin (EC(50) = 0.02 microM). Little or no effect on lick rate was observed in response to the full TRPV1 agonist olvanil. Capsaicin lick rates of wild-type and transient receptor potential melastatin-5 (TRPM5) knockout mice were equivalent, indicating that TRPM5, a critical component of aversive signaling for many bitter tastants, did not contribute to the capsaicin taste response. The selective TRPV1 antagonists N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (10 microM) and (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (AMG9810) (10 microM) effectively blocked capsaicin- and piperine-mediated lick suppression. However, (E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)-N-phenylprop-2-enamide (SB 366791) and capsazepine, also TRPV1 antagonists, were without effect at test concentrations of up to 30 and 100 microM, respectively. Our results demonstrate that TRPV1-mediated oral aversiveness presents a pharmacologic profile differing from what has been reported previously for TRPV1 pain signaling and, furthermore, that aversive tastes can be evaluated and controlled pharmacologically.
authors.affiliation: Discovery Research, RedPoint Bio Corporation, Ewing, New Jersey, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Long
authors.forename: Heather R
authors.initials: HR
authors.lastname: Devantier
authors.forename: Francis X
authors.initials: FX
authors.lastname: Brennan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Bryant
authors.forename: F Raymond
authors.initials: FR
authors.lastname: Salemme
authors.forename: R Kyle
authors.initials: RK
authors.lastname: Palmer
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000284:Administration, Oral; D000470:Alkaloids; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D052117:Benzodioxoles; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002211:Capsaicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000235:genetics; D050916:TRPV Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013649:Taste / Q000187:drug effects*
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D000470:Alkaloids; D000813:Anilides; D052117:Benzodioxoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002934:Cinnamates; D004224:Diterpenes; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011719:Pyrazines; D011725:Pyridines; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C024353:resiniferatoxin; C071423:capsazepine; D002211:Capsaicin; C008922:piperine