P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity.
BACKGROUND
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterised by abdominal pain and bloating in association with altered bowel movements. Its pathogenesis and the underlying molecular mechanisms of visceral hyperalgesia remain elusive. Recent studies of somatic and other visceral pain models suggest a role for purinergic signalling mediated by the P2X receptor (P2XR) family.


OBJECTIVE
To examine the role of P2XR signalling in the pathogenesis in a rat model of IBS-like visceral hyperalgesia.


METHODS
Visceral hypersensitivity was induced by colonic injection of 0.5% acetic acid (AA) in 10-day-old rats and experiments were conducted at 8 weeks of age. Dorsal root ganglion (DRG) neurons innervating the colon were labelled by injection of DiI (1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate) fluorescence into the colon wall.


RESULTS
Visceral hypersensitivity was reversed by TNP-ATP (2'-(or-3')-O-(trinitrophenyl) ATP), a potent P2X1, P2X3 and P2X2/3 receptor antagonist. Rapid application of ATP (20 microM) induced a fast inactivating current in colon-specific DRG neurons from both control and AA-treated rats. There was a twofold increase in the peak ATP responses in neurons from AA-treated rats. These currents were sensitive to TNP-ATP (100 nM). Under current-clamped conditions, ATP evoked a larger membrane depolarisation in neurons from neonatal AA-treated rats than in controls. P2X3R protein expression was significantly enhanced in colon-specific DRGs 8 weeks after neonatal AA treatment.


CONCLUSIONS
These data suggest that the large enhancement of P2XR expression and function may contribute to the maintenance of visceral hypersensitivity, thus identifying a specific neurobiological target for the treatment of chronic visceral hyperalgesia.
Xu
G-Y
GY
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA. gyxu@utmb.edu
Shenoy
M
M
Winston
J H
JH
Mittal
S
S
Pasricha
P J
PJ
D019342:Acetic Acid; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002908:Chronic Disease; D003106:Colon / Q000294:innervation; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D043183:Irritable Bowel Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058469:Receptors, Purinergic P2X; D015398:Signal Transduction; D015854:Up-Regulation
D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D019342:Acetic Acid