Gastroenterology

Gastroenterology

Volume 126, Issue 3, March 2004, Pages 683-692
Gastroenterology

Clinical-alimentary tract
The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-d-aspartate receptor

https://doi.org/10.1053/j.gastro.2003.11.047Get rights and content

Abstract

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, 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.

Section snippets

Subjects

All subjects were healthy adult volunteers with normal medical assessments, which included a detailed health questionnaire,31 and none were taking any medication. Esophageal manometry (Polygram for Windows 1995; Synectics Medical, Enfield, Middlesex, United Kingdom) was normal in all subjects. Written informed consent was obtained after the nature and the purpose of the trial had been explained. All protocols reported were presented to and approved by the Salford and Trafford Research Ethics

Protocol 1

All subjects completed the 2 studies. Pulse rate, arterial blood pressure, and ECG recordings were unchanged both during and following either saline or ketamine infusion.

On completion of the ketamine infusion, pain threshold in the esophagus (mean, 7.22 ± 3.6 mA ketamine vs. 0.66 ± 3.3 mA saline, P = 0.03, Wilcoxon; Figure 1A) and foot (mean, 1.44 ± 3.7 mA ketamine vs. −2.2 ± 2.95 mA saline, P = 0.05, Wilcoxon; Figure 1B), were increased. However, this effect had disappeared within 30 minutes

Discussion

Our results show that the hypersensitivity induced in the proximal esophagus by acid infusion in the distal esophagus is both prevented and reversed by the NMDA receptor antagonist ketamine. This demonstrates that both the development and the maintenance of esophageal pain hypersensitivity in our model are dependent on the integrity of the NMDA receptor, which therefore suggests that the mechanism for this hypersensitivity is central sensitization.

Our study was designed to assess both the

Acknowledgements

The authors thank the staff of the Gastrointestinal Physiology Unit and Pharmacy Additive Unit at Hope Hospital, Manchester, United Kingdom, for their assistance.

References (72)

  • S. Ilkjaer et al.

    Effect of systemic N-methyl-d-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans

    Br J Anaesth

    (1996)
  • T. Warncke et al.

    Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in mana double-blind, cross-over comparison with morphine and placebo

    Pain

    (1997)
  • T. Graven-Nielsen et al.

    Ketamine reduces muscle pain, temporal summation and referred pain in fibromyalgia patients

    Pain

    (2000)
  • S. Sarkar et al.

    Contribution of central sensitisation to the development of non-cardiac chest pain

    Lancet

    (2000)
  • J.A. Clements et al.

    Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans

    J Pharm Sci

    (1982)
  • J.A. Clements et al.

    Pharmacokinetics and analgesic effect of ketamine in man

    Br J Anaesth

    (1981)
  • E. Strauss et al.

    Assessing believable deficits of measures of attention and information processing capacity

    Arch Clin Neuropsychol

    (1994)
  • S. Sarkar et al.

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

    Gastroenterology

    (2003)
  • J.A. McRoberts et al.

    Role of peripheral N-methyl-d-aspartate (NMDA) receptors in visceral nociception in rats

    Gastroenterology

    (2001)
  • Q.P. Ma et al.

    Localization of N-methyl-d-aspartate NR2B subunits on primary sensory neurons that give rise to small-caliber sciatic nerve fibers in rats

    Neuroscience

    (2000)
  • T. Olivar et al.

    Differential effects of N-methyl-d-aspartate receptor blockade on nociceptive somatic and visceral reflexes

    Pain

    (1999)
  • S.V. Coutinho et al.

    Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors

    Brain Res

    (1996)
  • R.J. Traub et al.

    NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression in the spinal cord and the visceromotor reflex

    Neuroscience

    (2002)
  • Y. Ide et al.

    The effects of an intrathecal NMDA antagonist (AP5) on the behavioral changes induced by colorectal inflammation with turpentine in rats

    Life Sci

    (1997)
  • Q.Z. Zhai et al.

    Differential effects of N-methyl-d-aspartate receptor blockade on nociceptive somatic and visceral reflexes

    Pain

    (1999)
  • H. Vanegas et al.

    Prostaglandins and cyclooxygenases in the spinal cord

    Prog Neurobiol

    (2001)
  • D.W. Garrison et al.

    Viscerosomatic convergence onto feline spinal neurons from esophagus, heart and stomach fieldseffects of inflammation

    Pain

    (1992)
  • G.F. Gebhart et al.

    Visceral paina review of experimental studies

    Pain

    (1990)
  • F. Cervero

    Sensory innervation of the visceraperipheral basis of visceral pain

    Physiol Rev

    (1994)
  • J. Ritchie

    Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome

    Gut

    (1973)
  • J.E. Richter et al.

    Abnormal sensory perception in patients with esophageal chest pain

    Gastroenterology

    (1986)
  • M. Bradete et al.

    Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone

    Dig Dis Sci

    (1991)
  • D.A. Drosssman et al.

    ROME II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus

    (2000)
  • P. Bessou et al.

    Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli

    J Neurophysiol

    (1969)
  • J.N. Campbell et al.

    Sensitization of myelinated nociceptive afferents that innervate monkey hand

    J Neurophysiol

    (1979)
  • S.N. Raja et al.

    Evidence for different mechanisms of primary and secondary hyperalgesia following heat injury to the glabrous skin

    Brain

    (1984)
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    Supported by grants from the Peel Research Trust, the Golden Charitable Trust, and the Mason Medical Foundation and a grant from the Lord Dowding Fund for Humane Research (to A.R.H.).

    1

    R.W. is a Digestive Disorders Foundation Alimentary Pharmacology & Therapeutics Clinical Research Fellow, University of Manchester.

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