The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans.
OBJECTIVE
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.
Sarkar
Sanchoy
S
Department of GI Science, Clinical Sciences Building, University of Manchester, Hope Hospital, Salford M6 8HD, UK.
Hobson
Anthony R
AR
Hughes
Andrew
A
Growcott
Jim
J
Woolf
Clifford J
CJ
Thompson
David G
DG
Aziz
Qasim
Q
D000143:Acids / Q000494:pharmacology*; D000328:Adult; D018592:Cross-Over Studies; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects*; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D014781:Viscera / Q000187:drug effects* / Q000503:physiopathology*
D000143:Acids; C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype