title: Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally separated rats.
abstract: Irritable bowel syndrome is in part characterized by an increased sensitivity to colonic distension. Stress is an important trigger factor for symptom generation. We hypothesized that stress induces visceral hypersensitivity via mast cell degranulation and transient receptor ion channel 1 (TRPV1) modulation. We used the rat model of neonatal maternal separation (MS) to investigate this hypothesis. The visceromotor response to colonic distention was assessed in adult MS and non-handled (NH) rats before and after acute water avoidance (WA) stress. We evaluated the effect of the mast cell stabilizer doxantrazole, neutralizing antiserum against the mast cell mediator nerve growth factor (NGF) and two different TRPV1 antagonists; capsazepine (non-specific) and SB-705498 (TRPV1-specific). Immunohistochemistry was used to assess post-WA TRPV1 expression in dorsal root ganglia and the presence of immunocytes in proximal and distal colon. Retrograde labelled and microdissected dorsal root ganglia sensory neurons were used to evaluate TRPV1 gene transcription. Results showed that acute stress induces colonic hypersensitivity in MS but not in NH rats. Hypersensitivity was prevented by prestress administration of doxantrazole and anti-NGF. Capsazepine inhibited and SB-705498 reversed poststress hypersensitivity. In MS rats, acute stress induced a slight increase in colonic mast cell numbers without further signs of inflammation. Post-WA TRPV1 transcription and expression was not higher in MS than NH rats. In conclusion, the present data on stress-induced visceral hypersensitivity confirm earlier reports on the essential role of mast cells and NGF. Moreover, the results also suggest that TRPV1 modulation (in the absence of overt inflammation) is involved in this response. Thus, mast cells and TRPV1 are potential targets to treat stress-induced visceral hypersensitivity.
authors.affiliation: Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. R.vandenwijngaard@AMC.UVA.NL
authors.forename: R M
authors.initials: RM
authors.lastname: van den Wijngaard
authors.forename: T K
authors.initials: TK
authors.lastname: Klooker
authors.forename: O
authors.initials: O
authors.lastname: Welting
authors.forename: O I
authors.initials: OI
authors.lastname: Stanisor
authors.forename: M M
authors.initials: MM
authors.lastname: Wouters
authors.forename: D
authors.initials: D
authors.lastname: van der Coelen
authors.forename: D C
authors.initials: DC
authors.lastname: Bulmer
authors.forename: P J
authors.initials: PJ
authors.lastname: Peeters
authors.forename: J
authors.initials: J
authors.lastname: Aerssens
authors.forename: R
authors.initials: R
authors.lastname: de Hoogt
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: W J
authors.initials: WJ
authors.lastname: de Jonge
authors.forename: G E
authors.initials: GE
authors.lastname: Boeckxstaens
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002404:Catheterization; D003106:Colon / Q000473:pathology; D004327:Drinking Behavior; D005260:Female; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology; D008407:Mast Cells / Q000502:physiology*; D008426:Maternal Deprivation; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D013315:Stress, Psychological / Q000503:physiopathology* / Q000523:psychology*; D013601:T-Lymphocytes / Q000502:physiology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014508:Urea; D020932:Nerve Growth Factor; C071423:capsazepine; D002211:Capsaicin