title: Experimental colitis alters expression of 5-HT receptors and transient receptor potential vanilloid 1 leading to visceral hypersensitivity in mice.
abstract: Abnormalities of primary afferent nerve fibers are strongly associated with the visceral hypersensitivity state in inflammatory bowel disease. Hypersensitivity of afferent fibers occurs during inflammation. Therefore, to gain an insight into the alterations to receptors and channels expressed in primary afferent neurons, the current study aimed to investigate the time-dependent dynamic changes in levels of 5-hydroxytryptamine (5-HT)(3) receptors, 5-HT(4) receptors, transient receptor potential vanilloid type 1 (TRPV1) channels, and 5-HT regulatory factors in dextran sulfate sodium (DSS)-induced colitis model mice. 5-HT signaling molecules were detected by indirect staining with specific antibodies. TRPV1-immunoreactivity was detected by staining with fluorescein-conjugated tyramide amplification. To assess nociception, visceromotor responses (VMRs) to colorectal distension were measured by electromyography of abdominal muscles. Immunohistochemical analysis and VMRs to colorectal distention were measured during induction of DSS colitis (days 4 and 7). Inflammation led to downregulation of serotonin transporter immunoreactivities with concomitant increases in 5-HT and tryptophan hydroxylase-1-positive cell numbers. TRPV1-expressing nerve fibers gradually increased during DSS treatment. Abundant nonneuronal TRPV1-immunopositive cell-like structures were observed on day 7 of DSS treatment but not on day 4. The number of 5-HT(3) receptor-expressing nerve fibers in the mucosa was increased on day 7. On the other hand, the number of 5-HT(4) receptor-expressing nerve fibers in the mucosa decreased on day 7. We made the novel observation of increased expression of neuronal/nonneuronal TRPV1 channels and 5-HT(3) receptors, and decreased expression of 5-HT(4) receptors in the mucosa in a DSS-induced colitis model. Visceral hyperalgesia was observed on day 7 but not on day 4. A TRPV1 antagonist and a 5-HT(3) receptor antagonist attenuated the visceral hyperalgesia to the control level. The alterations of 5-HT signaling via 5-HT(3) receptors and of TRPV1 channels in mucosa may contribute to the visceral hypersensitivity in colitis model mice.
authors.affiliation: Laboratory of Pharmacology, Josai International University, Togane, Chiba, Japan. kenjiro@jiu.ac.jp
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Mee Wah
authors.initials: MW
authors.lastname: Lo
authors.forename: Takuji
authors.initials: T
authors.lastname: Hosoya
authors.forename: Kimihito
authors.initials: K
authors.lastname: Tashima
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takayama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
authors.forename: Syunji
authors.initials: S
authors.lastname: Horie
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004576:Electromyography; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000294:innervation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D059225:Nociception / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D017833:Visceral Afferents / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D002243:Carbolines; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011719:Pyrazines; D011725:Pyridines; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C090840:alosetron; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D016264:Dextran Sulfate; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase