P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity

G. Y. Xu, M. Shenoy, John Winston, S. Mittal, P. J. Pasricha

Research output: Contribution to journalArticle

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Abstract

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. Aims: 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 Dil (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′)-0- (trinitrophenyl) ATP), a potent P2X1, P2X3 and P2X2/3 receptor antagonist. Rapid application of ATP (20 μ.M) 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.

Original languageEnglish (US)
Pages (from-to)1230-1237
Number of pages8
JournalGut
Volume57
Issue number9
DOIs
StatePublished - Sep 2008

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Hyperalgesia
Acetic Acid
Hypersensitivity
Adenosine Triphosphate
Colon
Neurons
Irritable Bowel Syndrome
Spinal Ganglia
Purinergic P2X2 Receptors
Visceral Pain
Injections
Diagnosis-Related Groups
Abdominal Pain
Fluorescence
Maintenance
Membranes
Therapeutics
Proteins

ASJC Scopus subject areas

  • Gastroenterology

Cite this

P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. / Xu, G. Y.; Shenoy, M.; Winston, John; Mittal, S.; Pasricha, P. J.

In: Gut, Vol. 57, No. 9, 09.2008, p. 1230-1237.

Research output: Contribution to journalArticle

Xu, G. Y. ; Shenoy, M. ; Winston, John ; Mittal, S. ; Pasricha, P. J. / P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. In: Gut. 2008 ; Vol. 57, No. 9. pp. 1230-1237.
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abstract = "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. Aims: 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 Dil (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′)-0- (trinitrophenyl) ATP), a potent P2X1, P2X3 and P2X2/3 receptor antagonist. Rapid application of ATP (20 μ.M) 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.",
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