Submitted on May 19, 2006
Accepted on July 26, 2006
Serotonergic modulation of murine fundic tone
Lin Xue1, Michael Camilleri1, G. Richard Locke, III1, Jan A.J. Schuurkes2, Ann Meulemans2, Bernard J. Coulie2, Joseph H. Szurszewski1, and Gianrico Farrugia1*
1 Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
2 Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
* To whom correspondence should be addressed. E-mail: farrugia.gianrico{at}mayo.edu.
Background and aims: Fundic tone is maintained through a balance of excitatory and inhibitory input to fundic smooth muscle. The aim of this study was to determine the role of 5-HT and 5-HT receptors in modulating murine fundic tone. Methods: Muscle strips were prepared from murine fundus. Intracellular recordings were made from circular smooth muscle cells and the effect of 5-HT on tone and excitatory and inhibitory junction potentials evoked by electrical field stimulation (EFS) determined. Results: 5-HT induced a dose concentration-dependent contraction and smooth muscle depolarization that was tetrodotoxin resistant. The 5HT1B/D receptor antagonists GR127935 and BRL155172 significantly inhibited 5-HT induced contraction. The 5HT1B/D agonist sumatriptan contracted murine fundic muscle. The 5HT1A receptor agonist buspirone relaxed fundic smooth muscle and the relaxation was inhibited by WAY100135 but not by L-NNA or tetrodotoxin. 5-HT enhanced both the excitatory and inhibitory response to EFS. The 5HT3 receptor antagonist MDL72222 partly inhibited both the excitatory and inhibitory response elicited by EFS while the 5HT4 receptor antagonist GR113808 partly inhibited the EFS-evoked inhibitory response. The 5-HT reuptake inhibitor fluoxetine contracted smooth muscle strips, a contraction that was partially inhibited by GR127935 and abolished by tetrodotoxin. Conclusions: The data suggest that 5-HT released from neurons modulates murine fundic contractile activity through several different receptor subtypes. Sustained release of 5-HT maintains fundic tone through post junctional 5-HT1B/D receptors. 5-HT3 receptors modulate excitatory neural input to murine fundic smooth muscle and both 5-HT3 and 5-HT4 receptors modulate inhibitory neural input to murine fundic smooth muscle.
