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Journal of Pharmacology and Toxicology
Year: 2006  |  Volume: 1  |  Issue: 2  |  Page No.: 176 - 200

Effects of Receptor Polymodality on Co-transmission by Acetylcholine and Serotonin in the Afferent Neuronal Pathway of the Gut

R. Miftahof    

Abstract: Electrophysiological mechanisms of co-transmission by serotonin (5-HT) and acetylcholine (ACh) on mechanoelectrical activity of the gut were studied numerically. A mathematical model of the bursting primary sensory (AH) and motor (S) neurons linked in sequence and smooth muscle syncytium mimicked the afferent pathway of the enteric nervous plexus of the organ. The role of different receptor types, i.e., 5-HT type 3 and 4, nicotinic (nACh) and muscarinic cholinergic (μACh) and the effects of selective and non-selective receptor agonists/antagonists on the dynamics of nerve signal transduction and mechanical response in the tissue were analyzed. Results showed that selective stimulation of the 5-HT3 receptors by endogenous 5-HT reduced the threshold of activation of the mechanoreceptors by 17.6%. Conjoint excitation by serotonin of the 5-HT3 and 5-HT4 receptors located on the primary sensory (AH) and motor (S) neurons converted their regular firing pattern of electrical discharges to a beating mode. Activation confined to 5-HT3 receptors located on the somas of the AH and S type neurons, could not sustain normal electrical signal transduction between them. It required acetylcholine as a co-transmitter and a subsequent co-activation of the nACh receptors. Selective 5-HT3 receptor antagonists, e.g., Ondansetron and Granisetron, increased the threshold activation of the mechanoreceptors and inhibited dose-dependently the production of action potentials by AH neurons. 5-HT4 receptor agonists, e.g., TS-591, prucalopride and ML10302, applied alone onto the longitudinal smooth muscle of the gut did not have any effects on its electromechanical activity. However, excitation of the 5-HT4 in conjunction with μACh receptors evoked an increase in intensity of the electromechanical activity of the syncytium. GR113808A, a selective 5-HT4 antagonist, acting alone strongly inhibited smooth muscle contractions but its effect was overcome through the activation of the 5-HT3, nACh and μACh receptors. A non-selective strong 5-HT3 and weak 5-HT4 - receptor agonists, Cisapride, demonstrated a prominent effect on the AH neuron with no significant changes in the electrical activity of the S neuron. Cisapride depolarized the soma of AH neuron with the generation of high amplitude spikes. The drug caused twitch contractions of the longitudinal smooth muscle. Comparison of the theoretical results to in vivo and in vitro experimental data indicated satisfactory qualitative and quantitative agreement. The numerical investigations helped us reveal the intrinsic mechanisms of co-transmission by ACh and 5-HT and the role of receptor polymodality at the cellular and tissue levels that could not have been elucidated using the existing experimental in vivo or in vitro methods.

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