Clinical-alimentary tractThe development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-d-aspartate receptor☆
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)
- et al.
Evolving pathophysiologic models of functional gastrointestinal disorders
Gastroenterology
(2002) - et al.
Role of visceral afferent mechanisms in functional bowel disorders
Gastroenterology
(1990) - et al.
Basic and clinical aspects of visceral hyperalgesia
Gastroenterology
(1994) - et al.
Mediators and pharmacology of visceral sensitivityfrom basic to clinical investigations
Gastroenterology
(1997) An overview of the mechanisms of hyperalgesia
Pulm Pharmacol
(1995)- et al.
The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activationimplications for the treatment of post-injury pain hypersensitivity states
Pain
(1991) - et al.
Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurons following C fiber stimulation
Neuropharmacology
(1987) - et al.
A cure of wind-upNMDA receptor antagonists as potential analgesics
Trends Pharmacol Sci
(1990) - et al.
Activity-dependent neuronal plasticity following tissue injury and inflammation
Trends Neurosci
(1992) - et al.
Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects
Pain
(1995)
Effect of systemic N-methyl-d-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans
Br J Anaesth
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
Ketamine reduces muscle pain, temporal summation and referred pain in fibromyalgia patients
Pain
Contribution of central sensitisation to the development of non-cardiac chest pain
Lancet
Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans
J Pharm Sci
Pharmacokinetics and analgesic effect of ketamine in man
Br J Anaesth
Assessing believable deficits of measures of attention and information processing capacity
Arch Clin Neuropsychol
The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans
Gastroenterology
Role of peripheral N-methyl-d-aspartate (NMDA) receptors in visceral nociception in rats
Gastroenterology
Localization of N-methyl-d-aspartate NR2B subunits on primary sensory neurons that give rise to small-caliber sciatic nerve fibers in rats
Neuroscience
Differential effects of N-methyl-d-aspartate receptor blockade on nociceptive somatic and visceral reflexes
Pain
Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors
Brain Res
NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression in the spinal cord and the visceromotor reflex
Neuroscience
The effects of an intrathecal NMDA antagonist (AP5) on the behavioral changes induced by colorectal inflammation with turpentine in rats
Life Sci
Differential effects of N-methyl-d-aspartate receptor blockade on nociceptive somatic and visceral reflexes
Pain
Prostaglandins and cyclooxygenases in the spinal cord
Prog Neurobiol
Viscerosomatic convergence onto feline spinal neurons from esophagus, heart and stomach fieldseffects of inflammation
Pain
Visceral paina review of experimental studies
Pain
Sensory innervation of the visceraperipheral basis of visceral pain
Physiol Rev
Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome
Gut
Abnormal sensory perception in patients with esophageal chest pain
Gastroenterology
Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone
Dig Dis Sci
ROME II. The functional gastrointestinal disorders. Diagnosis, pathophysiology and treatment: a multinational consensus
Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli
J Neurophysiol
Sensitization of myelinated nociceptive afferents that innervate monkey hand
J Neurophysiol
Evidence for different mechanisms of primary and secondary hyperalgesia following heat injury to the glabrous skin
Brain
Cited by (194)
Pain Management in Burn Patients: Pharmacologic Management of Acute and Chronic Pain
2024, Clinics in Plastic SurgeryThe effect of methadone on postoperative quality of recovery in patients undergoing laparoscopic cholecystectomy: A prospective, randomized, double blinded, controlled clinical trial
2019, Journal of Clinical AnesthesiaCitation Excerpt :Additionally, like other μ agonists, remifentanil administration may be related to the development of hyperalgesia and opioid tolerance [5]. Many mechanisms may contribute to these phenomena including the activation of excitatory N‑methyl‑d‑aspartate (NMDA) receptors [6–8]. An alternative approach to pain control with morphine following LC would be methadone administration.
Central sensitization in chronic pain and medically unexplained symptom research: A systematic review of definitions, operationalizations and measurement instruments
2019, Journal of Psychosomatic ResearchCitation Excerpt :This enhanced facilitation may lead to hyperexcitability of the neurons [81,126]. “A key step in the development of central sensitization is activation and modulation of the N-methyl-D-aspartate (NMDA) receptor in those dorsal horn neurons of the spinal cord that receive primary afferent input” [132]. The description of the definitions of CS, both the main theme and the four subthemes, in the publications on MUS do not differ from those in the publications on chronic pain.
Investigation of the brain-gut axis
2019, Clinical and Basic Neurogastroenterology and MotilityChronic abdominal pain in inflammatory bowel disease: A practical guide
2023, Frontline Gastroenterology
- ☆
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.