P2Y1R is involved in visceral hypersensitivity in rats with experimental irritable bowel syndrome

World J Gastroenterol. 2017 Sep 14;23(34):6339-6349. doi: 10.3748/wjg.v23.i34.6339.

Abstract

Aim: To evaluate the role of P2Y1R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.

Methods: A rat model of irritable bowel syndrome was generated by intra-colonic administration of acetic acid (AA) and assessed by histology and myeloperoxidase (MPO) activity assay. Then P2Y1R expression in the colonic tissue was detected by Western blot. In order to explore the regulatory role of P2Y1R in visceral hypersensitivity, an agonist (MRS2365) and an antagonist (MRS2179) of P2Y1R were intra-colonically administered and effects were tested through a colorectal distension test. The abdominal withdrawal reflex and abdominal electromyography were tested during the course.

Results: Model assessment tests showed an obvious inflammatory reaction that appeared on the 2nd d after the AA injection, and the inflammatory reaction gradually recovered and almost disappeared on the 7th d. The model finished on day 8 and showed a clear feature of IBS that had no organic lesion. The average expression of P2Y1R was significantly higher in the AA group than in the naïve group (0.319 ± 0.02 vs 0.094 ± 0.016, P < 0.001). MRS2365 could effectively raise the colonic hypersensitivity status at intervention doses of 10 (AUC value from 0.30 ± 0.089 to 1.973 ± 0.127 mv·s, P < 0.01) and 100 μmol/L (AUC value from 0.290 ± 0.079 to 1.983 ± 0.195 mv·s, P < 0.01); MRS2179 could effectively reduce the hypersensitivity status at intervention dose of 100 μmol/L (from a mean baseline AUC value of 1.587 ± 0.099 mv·s to 0.140 ± 0.089 mv·s, P < 0.0001). Differences between the MRS2179 group (1.88 ± 1.45) and either the MRS2365 group (3.96 ± 0.19) or the combined treatment (MRS2179 and MRS2365) group (3.28 ± 0.11) were significant (P < 0.01).

Conclusion: P2Y1R plays a regulatory role in visceral hypersensitivity in rats with experimental IBS. Specific antagonists of P2Y1R may have potential therapeutic value in treating abdominal pain in IBS.

Keywords: Irritable bowel syndrome; P2Y1 receptor; Regulation; Therapy; Visceral hypersensitivity.

MeSH terms

  • Acetic Acid / toxicity
  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / pharmacology
  • Animals
  • Colon / drug effects
  • Colon / pathology
  • Disease Models, Animal
  • Electromyography
  • Humans
  • Irritable Bowel Syndrome / chemically induced
  • Irritable Bowel Syndrome / pathology*
  • Male
  • Nociception / drug effects
  • Nociceptive Pain / pathology*
  • Pain Measurement / methods
  • Pain Threshold*
  • Purinergic P2Y Receptor Agonists / pharmacology
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2Y1 / metabolism*
  • Reflex / drug effects
  • Visceral Pain / pathology*

Substances

  • (N)-methanocarba-2MeSADP
  • N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate
  • P2ry1 protein, rat
  • Purinergic P2Y Receptor Agonists
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y1
  • Adenosine Diphosphate
  • Acetic Acid