The Development and Maintenance of Human Visceral Pain Hypersensitivity Is Dependent on the N-Methyl-D-Aspartate Receptor

Robert Paul Willert, Clifford J. Woolf, Anthony Robert Hobson, Claire Delaney, David G. Thompson, Qasim Aziz

    Research output: Contribution to journalArticlepeer-review


    Background & Aims: 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, cross-over 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 hyper-sensitivity 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 hyper-sensitivity 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.
    Original languageEnglish
    Pages (from-to)683-692
    Number of pages9
    Issue number3
    Publication statusPublished - Mar 2004


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