title: Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats.
abstract: Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK(1) receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation.
authors.affiliation: Programa de Pós-graduação em Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, RS, Brazil Departmento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, RS, Brazil Programa de Pós-graduação em Ciências Biológicas, Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, RS, Brazil Programa de Pós-graduação em Farmacologia Bioquímica e Molecular, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Carin
authors.initials: C
authors.lastname: Hoffmeister
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.forename: Mateus Fortes
authors.initials: MF
authors.lastname: Rossato
authors.forename: Sara Marchesan
authors.initials: SM
authors.lastname: de Oliveira
authors.forename: Marcus Vinícius
authors.initials: MV
authors.lastname: Gomez
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000178:Acrylamides / Q000627:therapeutic use; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D000975:Antioxidants / Q000009:adverse effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D002211:Capsaicin / Q000008:administration & dosage; D002934:Cinnamates / Q000627:therapeutic use; D004205:Cromolyn Sodium / Q000008:administration & dosage; D004195:Disease Models, Animal; D004224:Diterpenes / Q000493:pharmacokinetics; D004487:Edema / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D016670:Gabexate / Q000627:therapeutic use; D006632:Histamine / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D008784:Methysergide / Q000008:administration & dosage; D010146:Pain / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D011398:Promethazine / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage; D050916:TRPV Cation Channels / Q000378:metabolism*; D014316:Tritium / Q000493:pharmacokinetics; D014527:Uric Acid / Q000009:adverse effects*
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D000813:Anilides; D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D000975:Antioxidants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002934:Cinnamates; D004224:Diterpenes; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D015842:Serine Proteinase Inhibitors; D012702:Serotonin Antagonists; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014316:Tritium; D014527:Uric Acid; D012701:Serotonin; D016670:Gabexate; D006632:Histamine; C024353:resiniferatoxin; D011451:Prostaglandin-Endoperoxide Synthases; D011398:Promethazine; D004205:Cromolyn Sodium; D002211:Capsaicin; D008784:Methysergide