The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans

Gastroenterology. 2003 Jan;124(1):18-25. doi: 10.1053/gast.2003.50022.


Background & aims: Central sensitization, an activity-dependent increase in spinal cord neuronal excitability, has been shown to contribute to esophageal pain hypersensitivity. Prostaglandin E2 (PGE(2)) is a mediator in both peripheral and central sensitization, in part via the prostaglandin E2 receptor-1 (EP-1), and may be a potential target for treating visceral pain. The purpose of this study was to determine whether acid-induced pain hypersensitivity within the non-acid-exposed esophagus (secondary hyperalgesia) is mediated by PGE(2) activation of the EP-1 receptor.

Methods: Twelve healthy male subjects participated in a randomized, placebo-controlled crossover study. Upper esophageal pain thresholds (PTs) to electrical stimulation were determined, and either the EP-1 antagonist ZD6416 or a placebo was orally administered. One-hour after dosing, acid or saline (0.15 mol/L) was infused into the lower esophagus for 30 minutes. Upper esophageal PT was monitored for 120 minutes after infusion.

Results: Except in 1 subject (who was excluded), the pH in the upper esophagus remained above 5 throughout all studies. In 8 subjects, ZD6416 attenuated the reduction in PT in the upper esophagus normally induced by acid infusion into the lower esophagus (area under curve [AUC]: -11.9 +/- 2.5 and 6.4 +/- 6.7 for placebo and ZD6416, respectively; P < 0.01). After saline infusion, the effects of ZD6416 and placebo were similar (AUC: 9.9 +/- 6 and 4.1 +/- 2, respectively; P = 0.8). Three subjects had no reduction in PT to acid infusion with placebo and were excluded at post hoc analysis.

Conclusions: The attenuation of secondary esophageal hyperalgesia by ZD6416 suggests that PGE(2), via the EP-1 receptor, contributes to human visceral pain hypersensitivity.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / pharmacology*
  • Adult
  • Cross-Over Studies
  • Esophagus / drug effects
  • Esophagus / metabolism
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Hyperalgesia / chemically induced
  • Hyperalgesia / physiopathology
  • Male
  • Middle Aged
  • Pain / physiopathology*
  • Pain Threshold / drug effects*
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / metabolism*
  • Receptors, Prostaglandin E, EP1 Subtype
  • Viscera / drug effects*
  • Viscera / physiopathology*


  • Acids
  • PTGER1 protein, human
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype