Gastroenterology

Gastroenterology

Volume 123, Issue 4, October 2002, Pages 969-977
Gastroenterology

Clinical–Alimentary Tract
Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron,☆☆,

https://doi.org/10.1053/gast.2002.35990Get rights and content

Abstract

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 H215O 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.

GASTROENTEROLOGY 2002;123:969-977

Section snippets

IBS patients

Patients were required to meet Rome I criteria for IBS,19 and be clinically and endoscopically without inflammatory or other structural intestinal disease. Patients recruited by advertisement and from the UCLA Functional Bowel Center were assessed during a 1-week screening period. Before screening, all patients gave informed consent in compliance with Food and Drug Administration requirements. Subjects were excluded during screening if they had a major psychiatric disorder, or scored >63 on any

Clinical characteristics of the treatment groups

There were no statistically significant differences between the Alos group (n = 20) and the placebo group (n = 17) in age (mean age, 39.2 vs. 40.7 years), gender (% females 45 vs. 53), baseline intensity ratings of IBS symptoms (7.4 ± 1.1 vs. 7.6 ± 1.0; maximum of scale, 20), and bowel habit (% diarrhea-predominance, 65 vs. 47). Baseline symptom ratings were not significantly different in subjects who received Alos at a dose of 1 mg twice daily and those receiving the higher doses of 2–4 mg

Discussion

The main findings of the current study are as follows: (1) Compared with placebo, Alos treatment reduced rCBF in ventromedial PFC, infragenual cingulate, hypothalamus, ventral striatum, and amygdala, all structures of the EMS, most of which contain 5-HT3Rs.12, 26 Drug-induced deactivations were most consistent for the right amygdala, were strongest in the baseline condition, and weakest during the rectal distention. Similarly, deactivation of cortical regions was observed in the 3 scans before,

Acknowledgements

The authors thank Drs. Charles Brown, Dan Silverman, Tony Lembo, Ronnie Fass, and Max Schmulson for help with performance of the studies; to the staff of the PET facilities Francine Aguilar, Priscilla Contreras, Dr. Ali Khonsary, Kristine Coyle, Der-Jen Liu, Larry Pang, Nayda Quinones, Josephine Ribe, and Ron Sumida; to Dr. William Blahd for his support; and to Teresa Olivas for her valuable preparation of the manuscript.

References (43)

  • R Bandler et al.

    Brain mediation of active and passive emotional coping

  • EA Mayer et al.

    Basic and clinical aspects of visceral hyperalgesia

    Gastroenterology

    (1994)
  • S Berman et al.

    Gender differences in regional brain response to visceral pressure in IBS patients

    Eur J Pain

    (2000)
  • H Mertz et al.

    Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distension

    Gastroenterology

    (2000)
  • B Bonaz et al.

    Central processing of rectal pain in IBS patients: an fMRI study (abstr)

    Gastroenterology

    (2000)
  • JR. Augustine

    Circuitry and functional aspects of the insular lobe in primates including humans

    Brain Res Rev

    (1996)
  • G Bush et al.

    Cognitive and emotional influences in anterior cingulate cortex

    Trends Cognitive Sci

    (2000)
  • JA van Hooft et al.

    5-HT3 receptors and neurotransmitter release in the CNS: a nerve ending story?

    Trends Neurosci

    (2000)
  • GF Gebhart et al.

    Vagal modulation of nociception

    Am Pain Soc J

    (1992)
  • EA. Mayer

    Emerging disease model for functional gastrointestinal disorders

    Am J Med

    (1999)
  • LX Cubeddu et al.

    Efficacy of ondansetron (GR38032F) and the role of serotonin in cisplatin-induced nausea and vomiting

    N Engl J Med

    (1990)
  • Cited by (133)

    • Psychological comorbidity in gastrointestinal diseases: Update on the brain-gut-microbiome axis

      2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia

      2015, Life Sciences
      Citation Excerpt :

      The normalized BPND image was spatially smoothed in three dimensions using an 8-mm full-width half-maximum Gaussian kernel. The ROIs were chosen based on previous studies of gastrointestinal symptoms [2,3,20]. We defined the ROIs of the midbrain, thalamus, caudate, putamen, amygdala, and hippocampus using the Wake Forest University Pick Atlas [1] and extracted the mean BPND in each ROI.

    • Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome

      2012, NeuroImage
      Citation Excerpt :

      Inline Supplementary Fig. S1 can be found online at http://dx.doi.org/10.1016/j.neuroimage.2012.08.028. Participants were then positioned in a GE Advance NXi PET camera and a 5-minute transmission scan was done as previously reported (Berman et al., 2002a). Emission data were acquired for 20 min and reconstructed using the OSEM method to generate an image of relative glucose metabolism during the auditory–visual vigilance task performance.

    View all citing articles on Scopus

    Address requests for reprints to: Emeran A. Mayer, M.D., CURE Digestive Diseases Research Center/Neuroenteric Disease Program, UCLA Division of Digestive Diseases, GLA VA HS, Building 115, Room 223, 11301 Wilshire Boulevard, Los Angeles, California 90073. e-mail: [email protected]; fax: (310) 794-2864.

    ☆☆

    Supported by NIH grants DK 48351 (to E.A.M.), NR 04881 (to B.D.N.), AR 46122 (to L.C.) and funds from Glaxo Wellcome, Inc., Research Triangle Park, North Carolina.

    Dr. Mayer is a member of GSK IBS Advisory Board and has received grants for basic and clinical projects from GSK.

    View full text