Original Report| Volume 12, ISSUE 2, P297-303, February 2011

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Effects of the N-Methyl-D-Aspartate Receptor on Temporal Summation of Second Pain (Wind-up) in Irritable Bowel Syndrome

Published:December 13, 2010DOI:


      Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the pathophysiological mechanisms of the pain and hypersensitivity are not well understood. IBS patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting that central hyperalgesic mechanisms may be involved. In the current study, during the wind-up testing session, a series of 6 heat pulses were presented with an interstimulus interval (ISI) of 3 seconds. Following the 1st, 3rd, and 6th thermal stimuli, subjects were asked to rate the late thermal sensation or second pain. IBS patients who demonstrated temporal summation of pain (TSSP) then received dextromethorphan and placebo in a randomized, double-blind, fashion to block wind-up. The results showed: 1) a subset of IBS patients, but not controls, showed TSSP in response to a series of noxious heat pulses; and 2) TSSP was blocked by administration of dextromethorphan, an NMDA receptor antagonist. In summary, these findings further elucidate mechanisms of somatic hypersensitivity in a subset of IBS patients. Our results also support an etiologic basis for abnormal NMDA receptor mechanisms in some IBS patients. Future studies are needed to determine if NMDA receptor antagonists may be used to treat IBS patients.


      This study evaluates temporal summation of second pain in a subset of IBS patients that is blocked by Dextromethorphan, an NMDA receptor antagonist. Theses results could lead to the use of an NMDA receptor antagonist in the treatment of pain in a subset of IBS patients.

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        • Beck A.T.
        • Steer R.A.
        • Garbin M.G.
        Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation.
        Clin Psychol Rev. 1988; 8: 77-100
        • Bouin M.
        • Meunier P.
        • Riberdy-Poitras M.
        • Poitras P.
        Pain hypersensitivity in patients with functional gastrointestinal disorders: A gastrointestinal-specific defect or a general systemic condition?.
        Dig Dis Sci. 2001; 46: 2542-2548
        • Chen L.
        • Malarick C.
        • Seefeld L.
        • Wang S.
        • Houghton M.
        • Mao J.
        Altered quantitative sensory testing outcome in subjects with opioid therapy.
        Pain. 2009; 143: 65-70
        • Coderre T.J.
        • Melzack R.
        Central neural mediators of secondary hyperalgesia following heat injury in rats: Neuropeptides and excitatory amino acids.
        Neurosci Lett. Sep. 1991; 30: 71-74
        • Cooper B.Y.
        • Vierck Jr., C.F.
        • Yeomans D.C.
        Selective reduction of second pain sensations by systemic morphine in humans.
        Pain. 1986; 24: 93-116
      1. Dubner R: Neuronal plasticity and pain following peripheral tissue inflammation or nerve injury. Proceedings of Vth World Congress on Pain. Pain Research and Clinical Management. Vol 5. Amsterdam: Elsevier, 1991, pp 263-276

        • Eide P.K.
        • Jorum E.
        • Stubhaug A.
        Relief of post-herpetic neuralgia with the N-methyl-D-aspartate acid receptor antagonist ketamine: A double blind, crossover comparison with morphine and placebo.
        Pain. 1994; 58: 347-355
        • Gebhart G.F.
        Pathobiology of visceral pain: Molecular mechanisms and therapeutic implications IV. Visceral afferent contributions to the pathobiology of visceral pain.
        Am J Physiol Gastrointest Liver Physiol. 2000; 278: G834-G838
        • Gebhart G.F.
        It’s chickens and eggs all over again: Is central reorganization the result or cause of persistent visceral pain?.
        Gastroenterology. 2007; 132: 1618-1620
        • Geel S.E.
        The fibromyalgia syndrome: Musculoskeletal pathophysiology.
        Semin Arthritis Rheum. 1994; 23: 347-353
        • Holtzer P.
        Capsacin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons.
        Pharmacol Rev. 1991; 43: 143-201
        • Li J.
        • Simone D.A.
        • Larson A.A.
        Windup leads to characteristics of central sensitization.
        Pain. 1999; 9: 75-82
        • Longstreth G.F.
        • Thompson W.G.
        • Chey W.D.
        • Houghton L.A.
        • Mearin F.
        • Spiller R.C.
        Functional bowel disorders.
        Gastroenterology. 2006; 130: 1480-1491
        • Maixner W.
        • Fillingim R.
        • Sigurdsson A.
        • Kincais S.
        • Silva S.
        Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain: Evidence for altered temporal summation of pain.
        Pain. 1998; 76: 71-81
        • Mayer E.A.
        • Bradesi S.
        • Chang L.
        • Spiegel B.M.
        • Bueller J.A.
        • Naliboff B.D.
        Functional GI disorders: from animal models to drug development.
        Gut. 2008; 57: 384-404
        • Mayer E.A.
        • Gebhart G.F.
        Basic and clinical aspects of visceral hyperalgesia.
        Gastroenterology. 1994; 107: 271-293
        • Price D.D.
        Characterizing Central Mechanisms Of Pathological Pain States By Sensory Testing And Neurophysiologic Analysis. Pain and Central Nervous System Disease: The Central Pain Syndromes, Vol 8.
        Raven Press, New York, NY1991 (pp 103-115)
        • Price D.D.
        Psychological Mechanisms of Pain and Analgesia. Progress in Pain Research and Management, Vol 15.
        IASP Press, Seattle, WA1999
        • Price D.D.
        • Craggs J.G.
        • Zhou Q.
        • Verne G.N.
        • Perstein W.M.
        • Robinson M.E.
        Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: Evidence from human psychophysics, animal models, and neuroimaging.
        Neuroimage. 2009; 47: 995-1001
        • Price D.D.
        • Bush F.M.
        • Long S.
        • Harkins S.W.
        A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales.
        Pain. 1994; 56: 217-226
        • Price D.D.
        • Harkins S.W.
        The combined use of visual analogue scales and experimental pain in providing standardized measurement of clinical pain.
        Clin J Pain. 1987; 3: 1-8
        • Price D.D.
        • Hu J.W.
        • Dubner R.
        Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses.
        Pain. 1977; 3: 57-68
        • Price D.D.
        • Long S.
        • Huitt C.
        Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy.
        Pain. 1992; 49: 163-173
        • Spielberger C.D.
        • Gorusch R.L.
        • Lushene R.
        • Vagg P.R.
        • Jacobs G.A.
        Manual for the State-Trait Anxiety Inventory (Form Y1).
        Consulting Psychologists Press, Palo Alto, CA1983
        • Staud R.
        • Bovee C.E.
        • Robinson M.E.
        • Price D.D.
        Cutaneous C-fiber pain abnormalities of fibromyalgia patients are specifically related to temporal summation.
        Pain. 2008; 139: 315-323
        • Staud R.
        • Vierck C.J.
        • Robinson M.E.
        • Price D.D.
        Effects of the N-methyl-D-aspartate receptor antagonist Dextromethorphan on Temporal Summation of Pain are similar in Fibromyalgia Patients and Normal Controls.
        J of Pain. 2005; 6: 323-332
        • Torebjork H.E.
        • Hallin R.G.
        Identification of afferent C units in intact human skin nerves.
        Brain Res. 1974; 67: 387-403
        • Verne G.N.
        The public awareness of the prevalence and impact of irritable bowel syndrome in the United States: Perception versus reality.
        J Clin Gastroenterol. 2004; 38: 419-424
        • Verne G.N.
        • Himes N.C.
        • Robinson M.E.
        • Gopinath K.S.
        • Briggs R.W.
        • Crosson B.
        • Price D.D.
        Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome.
        Pain. 2003; 103: 99-110
        • Verne G.N.
        • Price D.D.
        Irritable bowel syndrome as a common precipitant of central sensitization.
        Curr Rheumatol Rep. 2002; 4: 322-328
        • Verne G.N.
        • Robinson M.E.
        • Vase L.
        • Price D.D.
        Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients.
        Pain. 2003; 105: 223-230
        • Watkins L.R.
        • Wiertelak E.P.
        • Furness L.E.
        • Maier S.F.
        Illness-induced hyperalgesia is mediated by spinal neuropeptides and excitatory amino acids.
        Brain Res. 1994; 664: 17-24
        • Yeomans D.C.
        • Cooper B.Y.
        • Vierck Jr., C.J.
        Effects of systemic morphine on responses of primates to first or second pain sensations.
        Pain. 1996; 66: 253-263
        • Yeomans D.C.
        • Proudfit H.K.
        Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: Electrophysiological evidence.
        Pain. 1996; 68: 141-150
        • Zhou Q.
        • Caudle R.M.
        • Price D.D.
        • Verne G.N.
        Phosphorylation of NMDA NR1 subunits in the myenteric plexus during TNBS induced colitis.
        Neurosci Lett. 2006; 406: 250-255
        • Zhou Q.
        • Caudle R.M.
        • Price D.D.
        • Verne G.N.
        Selective up-regulation of NMDA-NR1 receptor expression in myenteric plexus after TNBS induced colitis in rats.
        Mol Pain Jan. 2006; 17: 3
        • Zhou Q.
        • Caudle R.M.
        • Price D.D.
        • Verne G.N.
        Visceral and somatic hypersensitivity in a subset of rats following TNBS-Induced colitis.
        Pain. 2008; 134: 9-15
        • Zhou Q.
        • Fillingim R.B.
        • Riley J.L.
        • Malarkey W.B.
        • Verne G.N.
        Central and peripherial hypersensitivity in the irritable bowel syndrome.
        Pain. 2010; 148: 454-461
        • Zhou Q.
        • Fillingim R.B.
        • Riley J.R.
        • Verne G.N.
        Thermal hypersensitivity in a subset of irritable bowel syndrome patients.
        World J Gastroenterol. 2009; 15: 3254-3260
        • Zhou Q.
        • Price D.D.
        • Caudle R.M.
        • Verne G.N.
        Spinal NMDA NR1 subunit expression following transient TNBS colitis.
        Brain Res. 2009; 1279: 109-120
        • Zhou Q.
        • Price D.D.
        • Verne G.N.
        Reversal of visceral and somatic hypersensitivity in a subset of hypersensitive rats by intracolonic lidocaine.
        Pain. 2008; 139: 218-224
        • Zhou Q.
        • Souba W.W.
        • Croce C.M.
        • Verne G.N.
        MicroRNA-29a Regulates Intestinal Membrane Permeability in Patients with Irritable Bowel Syndrome.
        Gut. 2010; 59: 775-784
        • Zhou Q.
        • Verne G.N.
        NMDA receptor and colitis: Basic science and clinical implications.
        Rev Analgesia. 2008; 10: 33-43
        • Zhou Q.
        • Zhang B.
        • Verne G.N.
        Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome.
        Pain. 2009; 146: 41-46