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Activation of 5-HT3 receptors in the rat and mouse intestinal tract: a comparative study
Navinisha Chetty1, Helen R Irving, Ian M Coupar
1Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia.
Abstract:
This study provides a comprehensive evaluation of 5-HT(3) receptor functional distribution in both the rat and mouse intestinal tract. 5-HT(3A-S) receptor splice variant mRNA was expressed throughout the intestine of the rat and mouse; the 5-HT(3A-L) variant being more common in the rat.5-HT, m-CPB, 1-PBG and 2-methyl-5-hydroxytryptamine (2m5-HT) induced contraction in the jejunum, ileum, proximal colon and distal colon of the rat (pEC(50) range: 2m5-HT, 5.86+/-0.40 to m-CPB, 7.47+/-0.27) and mouse (pEC(50) range: 1-PBG, 5.34+/-0.06 to m-CPB, 6.49+/-0.14) in the presence of nontarget 5-HT receptor antagonists, methysergide (1 muM) and GR125487 (0.1 microM). The rank orders of potency in the four regions of the rat and mouse intestine were concordant with the accepted order and the responses to 5-HT were inhibited by ondansetron (0.1 microM).5-HT(3)-induced contractions to 5-HT were reduced by tetrodotoxin (1 microM). Pargyline (10 muM) and fluoxetine (1 microM) potentiated responses in the rat jejunum. Atropine (0.1 microM) potentiated 5-HT(3)-induced responses in the rat jejunum (E(max) 49-65%), but attenuated responses in most other regions of the rat and mouse (e.g. mouse ileum: E(max) 57-26%). In the rat jejunum, L-NAME (100 microM) mimicked the effect of atropine, hexamethonium (100 microM) suppressed 5-HT(3)-induced responses, but tachykinin receptor antagonists were without effect. It is concluded that functional 5-HT(3) receptors are present in nerves along the length of the rat and mouse intestinal tract. The mouse proximal colon was found to discriminate 5-HT(3) receptor agonist profiles better than any other region in the rat or mouse. The rat jejunum shows evidence of 5-HT uptake and inactivation processes as well as inhibitory nitrergic and nontachykinin excitatory pathways associated with the 5-HT(3)-induced response.
Insights
Functional 5-HT(3) receptors are present throughout the rat and mouse intestines, mediating contractions. The mouse proximal colon uniquely distinguishes 5-HT(3) receptor agonist profiles, while the rat jejunum exhibits complex neural pathways.
Area of Science:
- Pharmacology
- Neurogastroenterology
- Molecular Biology
Background:
- The distribution and function of serotonin 5-HT(3) receptors in the gastrointestinal tract are crucial for regulating motility and sensation.
- Understanding species-specific differences in receptor expression and function is vital for preclinical research.
Purpose of the Study:
- To comprehensively evaluate the functional distribution of 5-HT(3) receptors in the rat and mouse intestinal tract.
- To characterize the agonist potency and receptor pharmacology across different intestinal regions.
- To investigate the involvement of intrinsic neural pathways in 5-HT(3) receptor-mediated responses.
Main Methods:
- Quantitative analysis of 5-HT(3A-S) and 5-HT(3A-L) splice variant mRNA expression.
- In vitro pharmacological characterization of 5-HT(3) receptor agonists (5-HT, m-CPB, 1-PBG, 2m5-HT) and antagonists (ondansetron, methysergide, GR125487) in isolated intestinal segments.
- Investigation of the effects of neurotransmission modulators (tetrodotoxin, pargyline, fluoxetine, atropine, L-NAME) on 5-HT(3)-induced contractions.
Main Results:
- 5-HT(3A-S) mRNA was found throughout the rat and mouse intestine, with 5-HT(3A-L) more prevalent in rats.
- Selective 5-HT(3) receptor agonists induced contractions in all tested regions of both species, with varying potencies.
- The mouse proximal colon demonstrated superior discrimination of agonist profiles compared to other regions.
- The rat jejunum exhibited 5-HT uptake, inhibitory nitrergic pathways, and non-tachykinin excitatory pathways.
Conclusions:
- Functional 5-HT(3) receptors are expressed in nerves along the entire length of the rat and mouse intestinal tract.
- Significant regional differences in 5-HT(3) receptor pharmacology exist between rat and mouse intestines.
- The rat jejunum possesses complex neural regulatory mechanisms modulating 5-HT(3) receptor activity.
