Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron.

BACKGROUND & AIMS The 5-HT3 receptor (5-HT3R) antagonist Alosetron (Alos) reduces the symptoms of female patients with diarrhea-predominant irritable bowel syndrome (IBS); yet, the mechanism(s) underlying this effect remains incompletely understood. We determined the effect of Alos on regional cerebral blood flow (rCBF) in the absence and presence of rectal or sigmoid stimulation to evaluate 2 hypothesized mechanisms of therapeutic action: peripheral antinociception and inhibition of emotional motor system (EMS) regions in the brain. METHODS Forty-nine nonconstipated irritable bowel syndrome (IBS) patients (26 female) received H(2)(15)O positron emission tomography (PET) brain scans before a randomized, placebo-controlled, 3-week trial with Alos (1-4 mg twice daily). PET scans were repeated after treatment in 37 completers. We assessed rCBF during baseline, rectal distention, and anticipation of undelivered rectal distention. The 3 conditions were repeated after a series of noxious sigmoid distentions. Rectal (45 mm Hg) and sigmoid (60 mm Hg) distentions were performed with a computer-controlled barostat device. RESULTS Alos treatment, as compared with placebo, improved IBS symptoms and reduced rCBF in 5-HT3R containing regions of the EMS, but not in areas activated by pain. Reduction of rCBF appeared greatest in the absence of visceral stimulation, and was partially reversed by rectal or sigmoid distention. Symptom improvement across sessions was significantly correlated with rCBF decreases in the 5-HT3R-rich amygdala, ventral striatum, and dorsal pons. CONCLUSIONS Reduction in IBS symptoms correlated with a drug-induced reduction in the activity of central autonomic networks mediating emotional expression that was maximal in the absence of nociceptive input.

[1]  B. Olivier,et al.  5-HT3 receptor antagonists and anxiety; a preclinical and clinical review , 2000, European Neuropsychopharmacology.

[2]  E A Mayer,et al.  Basic and clinical aspects of visceral hyperalgesia. , 1994, Gastroenterology.

[3]  A. Randich,et al.  Vagal modulation of nociception , 1992 .

[4]  Gert Holstege,et al.  Chapter 1 The emotional motor system , 1996 .

[5]  C. Saper,et al.  The biological basis for mind body interactions , 2000 .

[6]  J. Galmiche,et al.  Alosetron does not affect the visceral perception of gastric distension in healthy subjects , 1994, Alimentary pharmacology & therapeutics.

[7]  A. Mangel,et al.  Review article: evaluation of drugs in experimental gut distension models , 1999, Alimentary pharmacology & therapeutics.

[8]  M. Hamon.  Central and peripheral 5-HT3 receptors , 1992 .

[9]  J. R. Augustine.  Circuitry and functional aspects of the insular lobe in primates including humans , 1996, Brain Research Reviews.

[10]  R Nieuwenhuys,et al.  The greater limbic system, the emotional motor system and the brain. , 1996, Progress in brain research.

[11]  J. Price,et al.  Brain mediation of active and passive emotional coping. , 2000, Progress in brain research.

[12]  Ronald Dubner,et al.  Ratio scales of sensory and affective verbal pain descriptors , 1978, Pain.

[13]  Gavin Kilpatrick,et al.  Binding of the 5-HT3 ligand, [3H]GR65630, to rat area postrema, vagus nerve and the brains of several species. , 1989, European journal of pharmacology.

[14]  Stuart W. G. Derbyshire,et al.  Meta-Analysis of thirty-four independent samples studied using PET reveals a significantly attenuated central response to noxious stimulation in clinical pain patients , 1999, Current review of pain.

[15]  B. Naliboff,et al.  Stress and the gastrointestinal tract. V. Stress and irritable bowel syndrome , 2001 .

[16]  M. Camilleri,et al.  Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial , 2000, The Lancet.

[17]  L. Derogatis,et al.  The SCL-90-R, Brief Symptom Inventory, and Matching Clinical Rating Scales. , 1999 .

[18]  M. Posner,et al.  Cognitive and emotional influences in anterior cingulate cortex , 2000, Trends in Cognitive Sciences.

[19]  M. Zhuo,et al.  Characterization of descending facilitation and inhibition of spinal nociceptive transmission from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. , 1992, Journal of neurophysiology.

[20]  E A Mayer,et al.  Emerging disease model for functional gastrointestinal disorders. , 1999, The American journal of medicine.

[21]  S. Derbyshire,et al.  Cerebral Activation in Patients With Irritable Bowel Syndrome and Control Subjects During Rectosigmoid Stimulation , 2001, Psychosomatic medicine.

[22]  M. Urban,et al.  Supraspinal contributions to hyperalgesia. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. K. Hartman,et al.  Effect of ondansetron, a 5-HT3 receptor antagonist, on the dynamic association between bulimic behaviors and pain thresholds , 1998, Pain.

[24]  J. Le Bas,et al.  Central processing of rectal pain in IBS patients: An fMRI study , 2000 .

[25]  Karl J. Friston,et al.  The Trouble with Cognitive Subtraction , 1996, NeuroImage.

[26]  H. Vijverberg,et al.  5-HT3 receptors and neurotransmitter release in the CNS: a nerve ending story? , 2000, Trends in Neurosciences.

[27]  D. Drossman,et al.  Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5‐HT3 receptor antagonist , 1999, Alimentary pharmacology & therapeutics.

[28]  M. E. Nevins,et al.  Antagonists at the serotonin-3 receptor can reduce the fear-potentiated startle response in the rat: evidence for different types of anxiolytic activity? , 1994, The Journal of pharmacology and experimental therapeutics.

[29]  M. Delvaux,et al.  Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome , 1998, Alimentary pharmacology & therapeutics.

[30]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[31]  L. Cubeddu,et al.  Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. , 1990, The New England journal of medicine.

[32]  I. Tracey,et al.  Cortical Processing of Human Somatic and Visceral Sensation , 1999, The Journal of Neuroscience.

[33]  P. Jhingran,et al.  Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome , 2001, American Journal of Gastroenterology.

[34]  R. Kessler,et al.  Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. , 2000, Gastroenterology.

[35]  B. Vogt,et al.  Contributions of anterior cingulate cortex to behaviour. , 1995, Brain : a journal of neurology.

[36]  M. Mandelkern,et al.  Gender differences in regional brain response to visceral pressure in IBS patients , 2000, European journal of pain.

[37]  M. Gershon.  Review article: roles played by 5‐hydroxytryptamine in the physiology of the bowel , 1999, Alimentary pharmacology & therapeutics.

[38]  L. Johnson,et al.  Physiology of the gastrointestinal tract , 2012 .

[39]  I. Yamaguchi,et al.  A mechanism of 5-HT3 receptor mediation is involved etiologically in the psychological stress lesion the stomach of the mouse. , 1994, The Journal of pharmacology and experimental therapeutics.

[40]  E A Mayer,et al.  Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. , 1997, Gastroenterology.

[41]  S. Caras,et al.  Cilansetron shows efficacy in non-constipated irrirable bowel syndrome patients independent of the definition of the patient population by Rome I or Rome II , 2001 .