Short-term sensitization of colon mechanoreceptors is associated with long-term hypersensitivity to colon distention in the mouse.
OBJECTIVE
Using a mouse model that reproduces major features of irritable bowel syndrome (long-lasting colon hypersensitivity without inflammation), we examined the contributions of 2 proteins, transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3 (ASIC3), on development of behavioral hypersensitivity and assessed the function of colon mechanoreceptors of hypersensitive mice.


METHODS
Visceral nociceptive behavior was measured as the visceromotor response (VMR) to colorectal distention (CRD) before and after intracolonic treatment with zymosan or saline. Colon pathology was assessed in parallel experiments by quantifying myeloperoxidase activity, intralumenal pH, and tissue histology. Electrophysiologic experiments were performed on naïve and zymosan-treated hypersensitive mice using an in vitro colon-pelvic nerve preparation.


RESULTS
Zymosan, but not saline, produced significant and persistent increases in the VMRs of control mice; zymosan produced nonsignificant increases in the VMRs in TRPV1 and ASIC3 knockout mice. Colon myeloperoxidase activity and pH were unaffected by either CRD or intracolonic treatments. Pelvic nerve mechanoreceptors recorded from zymosan-treated or naïve mice had similar sensitivity to stretch of the colon. When applied acutely, zymosan sensitized muscular/mucosal mechanoreceptors in both naïve and hypersensitive mice.


CONCLUSIONS
Zymosan produced sensitization of colon mechanoreceptors acutely in vitro and chronic (>or=7 weeks) behavioral hypersensitivity in the absence of inflammation. The behavioral hypersensitivity was partially dependent on both TRPV1 and ASIC3 because deletions of either of these genes blunted zymosan's effect, suggesting that these proteins may be important peripheral mediators for development of functional (ie, noninflammatory) visceral hypersensitivity.
Jones
R Carter W
RC
Medical Scientist Training Program, The University of Iowa, Iowa City, Iowa, USA.
Otsuka
Eiji
E
Wagstrom
Emily
E
Jensen
Chris S
CS
Price
Margaret P
MP
Gebhart
G F
GF
D062565:Acid Sensing Ion Channels; D000818:Animals; D003106:Colon / Q000294:innervation / Q000503:physiopathology; D004195:Disease Models, Animal; D004576:Electromyography; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D043183:Irritable Bowel Syndrome / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008465:Mechanoreceptors / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D015054:Zymosan