The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor.
OBJECTIVE
Visceral hypersensitivity is a common feature of functional gastrointestinal disorders. One speculated mechanism is an activity-dependent increase in spinal cord neuronal excitability (central sensitization), which is dependent on activation of the N-methyl-D-aspartate (NMDA) receptor. Our aims were to determine whether the development and maintenance of human visceral hypersensitivity is NMDA receptor mediated.


METHODS
Healthy subjects were studied using a randomized, double-blind, placebo-controlled, crossover design. Pain thresholds to electrical stimulation were determined both in the proximal esophagus and in the foot (control) before and after a 30-minute distal esophageal infusion of 0.15 mol/L HCl acid. Ketamine (NMDA receptor antagonist) or saline (vehicle) was given intravenously either prior to or following acid infusion, and pain thresholds were measured for the following 120 minutes. Protocol 1: In 6 subjects, the effect of ketamine in the esophagus was assessed without acid infusion. Protocol 2: In 14 subjects, ketamine was given prior to esophageal acid. Protocol 3: In 12 subjects, ketamine was given after esophageal acid.


RESULTS
Protocol 1: In the absence of esophageal acid, ketamine had no effect on either esophageal or foot pain thresholds (area-under-the-curve, [AUC] P = 0.36 esophagus, P = 0.34 foot, ANOVA) within 30 minutes of cessation of the infusion. Protocol 2: Acid-induced esophageal hypersensitivity was prevented by ketamine (AUC, P < 0.0001, ANOVA) without affecting foot pain thresholds (AUC, P = 0.06, ANOVA). Protocol 3: Ketamine delivered after acid reversed the induction of esophageal hypersensitivity induced by acid (AUC, P < 0.0001, ANOVA).


CONCLUSIONS
The induction and maintenance of acid-induced esophageal hypersensitivity is prevented and reversed by ketamine. This finding strongly indicates that central sensitization is a mechanism of visceral hypersensitivity.
Willert
Robert Paul
RP
GI Science Group, Hope Hospital, Salford, United Kingdom.
Woolf
Clifford J
CJ
Hobson
Anthony Robert
AR
Delaney
Claire
C
Thompson
David G
DG
Aziz
Qasim
Q
D000328:Adult; D019540:Area Under Curve; D001288:Attention / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004558:Electric Stimulation; D004947:Esophagus; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology; D005528:Foot; D006801:Humans; D006851:Hydrochloric Acid / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology* / Q000503:physiopathology* / Q000517:prevention & control; D007649:Ketamine / Q000009:adverse effects / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014781:Viscera
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D006851:Hydrochloric Acid