title: Gender-related differential effect of tachykinin NK2 receptor-mediated visceral hyperalgesia in guinea pig colon.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bellucci
authors.affiliation: Neurogastroenterology & Nutrition Department INRA/ESAP, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Buéno
authors.affiliation: Pharmacokinetics Department, Menarini Ricerche S.p.A., Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bugianesi
authors.affiliation: Pharmacokinetics Department, Menarini Ricerche S.p.A., Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Crea
authors.affiliation: Pharmacokinetics Department, Menarini Ricerche S.p.A., Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: D'Aranno
authors.affiliation: Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Meini
authors.affiliation: Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Santicioli
authors.affiliation: Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tramontana
authors.affiliation: Pharmacology Department, Menarini Ricerche S.p.A., Florence, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D003106:Colon / Q000378:metabolism*; D004151:Dipeptides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D018041:Receptors, Neurokinin-2 / Q000378:metabolism*; D012727:Sex Characteristics; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid; D059265:Visceral Pain / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D004151:Dipeptides; D018041:Receptors, Neurokinin-2; D013876:Thiophenes; C556791:ibodutant; D014302:Trinitrobenzenesulfonic Acid