Viscerosomatic Facilitation in a Subset of IBS Patients, an Effect Mediated by N-Methyl-D-Aspartate Receptors


      Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the pathophysiological mechanisms of the pain and hypersensitivity are incompletely understood. IBS patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting involvement of central hyperalgesic mechanisms. We tested the role of tonic peripheral impulse input by using both repetitive thermal stimuli to the leg and repetitive stimuli to the rectum. Changes in thermal/visceral pain sensitivity after nociceptive thermal/visceral repetitive stimulation were determined. A subset of IBS patients showed enhanced rectal/thermal pain sensitivity after repetitive thermal/rectal stimulation, respectively. IBS patients then received 60 mg dextromethorphan and placebo (diphenhydramine) in a randomized, double-blind, crossover trial. The results showed that 1) a subset of IBS patients had increased visceral/cutaneous hypersensitivity following a series of repetitive nociceptive stimuli and that 2) this increased pain sensitivity was blocked by administration of dextromethorphan. This is the first human study indicating that repetitive stimulation enhances a bidirectional mechanism of secondary hyperalgesia due to viscerosomatic facilitation in IBS patients. These unique findings elucidate mechanisms of somatic hypersensitivity in IBS patients and support an etiologic basis for abnormal N-methyl-D-aspartate receptor mechanisms that may be the target of future therapies for IBS.


      Repetitive stimulation enhances a bidirectional mechanism of secondary hyperalgesia due to viscerosomatic convergence in IBS patients. The findings elucidate unique mechanisms of somatic/visceral hypersensitivity in a subset of IBS patients and further support an etiologic basis for abnormal N-methyl-D-aspartate receptor mechanisms that may be future targets of therapies for IBS.

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        • Al-Chaer E.D.
        • Feng Y.
        • Willis W.D.
        Comparative study of viscerosomatic input onto postsynaptic dorsal column and spinothalamic tract neurons in the primate.
        J Neurophysiol. 1999; 82: 1876-1882
        • 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
        • Coderre T.J.
        • Melzack R.
        Central neural mediators of secondary hyperalgesia following heat injury in rats: Neuropeptides and excitatory amino acids.
        Neurosci Lett. 1991; 131: 71-74
        • Gallagher D.
        • Breckenridge J.
        • Steinmetz J.
        • Thompson L.
        The Beck Depression Inventory and Research Diagnostic Criteria: Congruence in an older population.
        J Consult Clin Psychol. 1983; 51: 945-946
        • Gebhart G.F.
        Visceral pain-peripheral sensitisation.
        Gut. 2000; 47: S54-S55
        • Geel S.E.
        The fibromyalgia syndrome: Musculoskeletal pathophysiology.
        Semin Arthritis Rheum. 1994; 23: 347-353
        • Gracely R.H.
        • Lynch S.A.
        • Bennett G.J.
        Painful neuropathy: Altered central processing maintained dynamically by peripheral input.
        Pain. 1992; 51: 175-194
        • Hancock M.B.
        • Willis W.D.
        • Harrison F.
        Viscerosomatic interactions in lumbar spinal cord of the cat.
        J Neurophysiol. 1970; 33: 46-58
        • Joe K.H.
        • Kim D.J.
        • Park B.L.
        • Yoon S.
        • Lee H.K.
        • Kim T.S.
        • Cheon Y.H.
        • Gwon D.H.
        • Lee H.W.
        • Namgung S.
        • Shin H.D.
        Genetic association of DRD2 polymorphisms with anxiety scores among alcohol-dependent patients.
        Biochem Biophys Res Commun. 2008; 371: 591-595
        • 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
        • Mackenzie J.
        Proc R Soc Med. 1909; 2: 75-80
        • Mackenzie J.
        Symptoms and their interpretation.
        Shaw, London, UK1909
        • Mayer E.A.
        • Gebhart G.F.
        Basic and clinical aspects of visceral hyperalgesia.
        Gastroenterology. 1994; 107: 271-293
      1. Milne RJ, Foreman RD, Giesler GJ Jr, Willis WD: Convergence of cutaneous and pelvic visceral nociceptive inputs onto primate spinothalamic neurons. Pain 11:163-183

        • 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.
        • Craggs J.G.
        • Zhou Q.
        • Verne G.N.
        • Perlstein 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.
        • Mao J.
        • Mayer D.
        Central consequences of persistent pain states.
        IASP Press, Seattle, WA1997
        • Price D.D.
        • Zhou Q.
        • Moshiree B.
        • Robinson M.E.
        • Verne G.N.
        Peripheral and central contributions to hyperalgesia in irritable bowel syndrome.
        J Pain. 2006; 7: 529-535
        • Sarlani E.
        • Greenspan J.D.
        Evidence for generalized hyperalgesia in temporomandibular disorders patients.
        Pain. 2003; 102: 221-226
        • 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 control subjects.
        J Pain. 2005; 6: 323-332
        • 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.
        • 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
        • Verne G.N.
        • Sen A.
        • Price D.D.
        Intrarectal lidocaine is an effective treatment for abdominal pain associated with diarrhea-predominant irritable bowel syndrome.
        J Pain. 2005; 6: 493-496
        • Villanueva L.
        • Cliffer K.D.
        • Sorkin L.S.
        • Le Bars D.
        • Willis Jr., W.D.
        Convergence of heterotopic nociceptive information onto neurons of caudal medullary reticular formation in monkey (Macaca fascicularis).
        J Neurophysiol. 1990; 63: 1118-1127
        • Zhou Q.
        • Caudle R.M.
        • Moshiree B.
        • Price D.D.
        • Verne G.N.
        Phosphorylation of NMDA NR1 subunits in the myenteric plexus during TNBS induced colitis.
        Neurosci Lett. 2006; 406: 250-261
        • Zhou Q.
        • Fillingim R.B.
        • Riley III, J.L.
        • Malarkey W.B.
        • Verne G.N.
        Central and peripheral hypersensitivity in the irritable bowel syndrome.
        Pain. 2010; 148: 454-461
        • Zhou Q.
        • Price D.D.
        • Callam C.S.
        • Woodruff M.A.
        • Verne G.N.
        Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain (wind-up) in irritable bowel syndrome.
        J Pain. 2011; 12: 297-303
        • 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.
        • Zhang B.
        • Verne G.N.
        Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome.
        Pain. 2009; 146: 41-46
        • Zighelboim J.
        • Talley N.J.
        • Phillips S.F.
        • Harmsen W.S.
        • Zinsmeister A.R.
        Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism.
        Dis Dis Sci. 1995; 40: 819-827
        • Willis W.D.
        • Al-Chaer E.D.
        • Quast M.J.
        • Westlund K.N.
        A visceral pain pathway in the dorsal column of the spinal cord.
        PNAS. 1999; 96: 7675-7679