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Gender-related differential effect of tachykinin NK2 receptor-mediated visceral hyperalgesia in guinea pig colon.
Bellucci, F; Buéno, L; Bugianesi, R; Crea, A; D'Aranno, V; Meini, S; Santicioli, P; Tramontana, M; Maggi, C A.
Afiliación
  • Bellucci F; Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
  • Buéno L; Neurogastroenterology & Nutrition Department INRA/ESAP, Toulouse, France.
  • Bugianesi R; Pharmacokinetics Department, Menarini Ricerche S.p.A., Rome, Italy.
  • Crea A; Pharmacokinetics Department, Menarini Ricerche S.p.A., Rome, Italy.
  • D'Aranno V; Pharmacokinetics Department, Menarini Ricerche S.p.A., Rome, Italy.
  • Meini S; Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
  • Santicioli P; Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
  • Tramontana M; Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
  • Maggi CA; Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
Br J Pharmacol ; 173(8): 1329-38, 2016 Apr.
Article en En | MEDLINE | ID: mdl-26758701
BACKGROUND AND PURPOSE: The tachykinin NK2 receptor antagonist ibodutant is under Phase III clinical investigation to treat female patients with irritable bowel syndrome. The aim of this study was to investigate the NK2 receptor-related gender specificity in a model of colitis. EXPERIMENTAL APPROACH: Colitis was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.5 mL, 30 mg·mL(-1) in 30% ethanol) in female and male guinea pigs. Electromyographic recording of the responses to colorectal distension (CRD) was made 3 days later. Ibodutant (0.33 , 0.65, 1.9 and 6.5 mg·kg(-1) ) was given s.c., 30 min before CRD. Release of neurokinin A and substance P from isolated mucosal and smooth muscle tissues following treatment with KCl (80 mM) or capsaicin (10 µM) was measured by EIA. Plasma pharmacokinetics of ibodutant following a single s.c. administration (0.73 or 2.1 mg·kg(-1) ) were measured over 24 h. KEY RESULTS: Ibodutant did not affect abdominal contractions in control animals. After TNBS-induced colitis, ibodutant prevented the increased visceral hypersensitivity to CRD in females, at lower doses than in males. Ibodutant pharmacokinetics did not differ between females and males. Tachykinins release was greater in smooth muscle than in mucosal samples. Capsaicin-stimulated release of tachykinins from inflamed mucosal samples from females was significantly lower than in males. CONCLUSIONS AND IMPLICATIONS: Ibodutant prevented abdominal nociception in a model of visceral hypersensitivity in guinea pigs with a greater efficacy in females than in males. Our results highlight a gender-related difference in colonic visceral hypersensitivity and mucosal nerve activation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Caracteres Sexuales / Receptores de Neuroquinina-2 / Colitis / Colon / Dolor Visceral / Hiperalgesia Tipo de estudio: Prognostic_studies Aspecto: Determinantes_sociais_saude Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2016 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Caracteres Sexuales / Receptores de Neuroquinina-2 / Colitis / Colon / Dolor Visceral / Hiperalgesia Tipo de estudio: Prognostic_studies Aspecto: Determinantes_sociais_saude Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2016 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido