Actions of Daiichi DQ-2511 on electrical and synaptic behavior of enteric neurons in the guinea-pig small intestine.

Intracellular recording of electrical and synaptic behavior of neurons in the enteric nervous system of guinea-pig small intestine was used to evaluate actions of DQ-2511 (3-[[[2-(3, 4-dimethoxyphenyl)ethyl]carbamoyl]methyl]amino-N-methylbenzamide). DQ-2511 is a new drug with gastrointestinal prokinetic action. DQ-2511 was most effective in the nanomolar range. The drug depolarized some of the neurons and this was accompanied by increased input resistance and augmented excitability. DQ-2511 in nanomolar concentrations increased the amplitude of fast excitatory postsynaptic potentials at nicotinic synapses. Slow inhibitory postsynaptic potentials, produced by release of norepinephrine from sympathetic postganglionic fibers, were suppressed by DQ-2511. This appeared to reflect presynaptic suppression of release of norepinephrine because postsynaptic responses to exogenously applied norepinephrine were unaffected. The results suggest that the prokinetic action of DQ-2511 on gastrointestinal transit might emerge from actions that augment excitatory synaptic transmission in the microcircuits of the enteric nervous system while suppressing inhibitory sympathetic neurotransmission.