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Comparative Study
. 2010 May;105(5):1173-80.
doi: 10.1038/ajg.2009.683. Epub 2009 Dec 15.

Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation

Meagan M Costedio  1 , Matthew D Coates, Elice M Brooks, Lisa M Glass, Eric K Ganguly, Hagen Blaszyk, Allison L Ciolino, Michael J Wood, Doris Strader, Neil H Hyman, Peter L Moses, Gary M Mawe
Affiliations
Comparative Study

Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation

Meagan M Costedio et al. Am J Gastroenterol. 2010 May.

Abstract

Objectives: Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal (GI) tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes.

Methods: Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without occurrence of constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and release levels were determined by enzyme immunoassay, and mRNA levels for the synthetic enzyme tryptophan hydroxylase-1 (TpH-1) and serotonin-selective reuptake transporter (SERT) were assessed by quantitative real-time reverse transcription PCR.

Results: CC was associated with increases in TpH-1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript levels were not altered. No changes in these elements of 5-HT signaling were detected in opiate-induced constipation (OIC).

Conclusions: These findings demonstrate that CC is associated with a pattern of altered 5-HT signaling that leads to increased 5-HT availability but does not involve a decrease in SERT expression. It is possible that increased 5-HT availability due to increased synthesis and release contributes to constipation due to receptor desensitization. Furthermore, the finding that elements of 5-HT signaling were not altered in the mucosa of individuals with OIC indicates that constipation as a condition does not lead to compensatory changes in 5-HT synthesis, release, or signal termination.

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Conflict of interest statement

Conflict of interest items

1. Guarantor of the manuscript

Gary M. Mawe, PhD

2. Roles of each author

Meagan M Costedio: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing

Matthew D Coates: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing

Elice M Brooks: tissue acquisition, data acquisition, and data analysis

Lisa M Glass: data acquisition, and data analysis.

Eric K Ganguly: aided in conception of the project, acquiring IRB approval, obtaining informed consent, and tissue acquisition.

Hagen Blaszyk: evaluation of sections and blind scoring of inflammation levels in the chronic constipation component of the study

Allison L. Ciolino: evaluation of sections and blind scoring of inflammation levels in the opiate constipation component of the study

Michael J Wood: involved in obtaining informed consent, and tissue acquisition.

Doris Strader: involved in obtaining informed consent, and tissue acquisition.

Neil H Hyman: involved in study conceptualization, planning, and identifying potential candidates for the chronic constipation component of the study.

Peter L Moses: involved in study conceptualization, planning, obtaining informed consent, and tissue acquisition, data analysis, and manuscript preparation and editing

Gary M Mawe: involved in study conceptualization, planning, data analysis, and manuscript preparation and editing.

All authors reviewed and approved the manuscript prior to submission.

4. Potential Competing Interests: None

Figures

Figure 1
Figure 1
Serotonin content and TpH1 transcript levels are increased in CC, but are not altered in opiate-induced constipation. (A) 5-HT content is significantly increased in CC (p=0.003). (B) No significant differences were detected in 5-HT levels of samples from individuals undergoing opiate therapy, with or without constipation (p>0.05 for each group vs control). (C) The transcript level for TpH-1 was significantly higher in RNA from CC samples as compared to healthy controls (p=0.028). (D) No significant differences were detected in TpH-1 RNA levels of samples from individuals in the opiate therapy groups as compared to controls (p>0.05 for each group vs control). n-values: A, 19, 16; B, 24, 20, 14; C, 22, 12; D, 13, 9, 13.
Figure 2
Figure 2
Serotonin release was elevated in CC samples under basal and stimulated conditions, but was not altered in mucosal samples from individuals with opiate-induced constipation. (A and B) 5-HT release was significantly increased under basal (p=0.009) and stimulated (p=0.03) conditions. (C and D) 5-HT was not significantly altered in samples from individuals undergoing opiate therapy under basal or stimulated conditions (p>0.05 for each group vs control). n-values: A, 23, 18; B, 23, 18 C, 19, 20, 15; D, 19, 20, 15.
Figure 3
Figure 3
No significant differences in the numbers of EC cells per gland (A, C) or the percentage of epithelial cells that were EC cells (B, D) were detected in the CC samples or in biopsies from individuals undergoing opiate therapy, as compared to healthy controls (p>0.05 for each group vs control). E: photomicrographs showing representative colonic glands that were used to quantify the EC cells in these preparations. n-values: A, 19, 11; B, 19, 11; C, 23, 25, 15; D, 23, 25, 15.
Figure 4
Figure 4
No significant differences in the SERT transcript levels were detected for CC samples (A) or opiate therapy samples as compared to healthy controls (p>0.05 for each group vs control). n-values: A, 22, 13; B, 13, 9, 13.
Figure 5
Figure 5
Schematic representation of the findings of this study. No changes were detected relative to control in samples from subjects with opiate induced constipation. Findings from subjects with chronic constipation revealed increased RNA levels in the rate limiting enzyme for 5-HT synthesis, tryptophan hydroxylase 1 (TpH1) in EC cells, increased mucosal 5-HT content indicating higher concentration of 5-HT in the EC cells, and increased 5-HT release under basal and stimulated conditions. Elements of 5-HT signaling that were not altered in chronic constipation included the number of EC cells and RNA levels for the 5-HT transporter.
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