Inhibition of spontaneous excitatory transmission induced by codeine is independent on presynaptic K+ channels and novel voltage-dependent Ca2+ channels in the guinea-pig nucleus tractus solitarius

The nucleus tractus solitarius (NTS) constitutes the cough reflex arc and is thought to be one of the main sites of codeine's action. We have previously demonstrated using the guinea-pig brainstem slice that codeine inhibits the solitary tract-evoked excitatory postsynaptic currents (EPSCs) in the second-order NTS neurons through activating the presynaptic K+ channels. For further understanding of modulation of synaptic transmission by the antitussive, the effects of codeine (0.3-3.0 mM) on spontaneous EPSCs (sEPSCs) and miniature EPSCs (mEPSCs) were investigated in the NTS neurons of guinea-pigs. Codeine decreased the frequency and amplitude of sEPSCs. This action of codeine was mimicked by specific μ and κ receptor agonists, and blocked by μ and κ receptor antagonists. An agonist of δ receptors was ineffective on sEPSCs. The inhibitory effect of codeine on sEPSCs persisted under perfusion of a K+ channel blocker, 4-aminopyridine. In the presence of tetrodotoxin or Cd2+ which blocks, respectively, the action potential-induced or voltage-dependent Ca2+ entry-induced transmitter release, codeine still had an inhibitory effect on the frequency of mEPSCs without any considerable effect on their amplitude. The present study demonstrates that codeine depresses spontaneous excitatory synaptic transmission in the NTS neurons via presynaptic μ and κ receptors that do not couple with K+ and Ca2+ channels. These results suggest inhibitory modulation of the local circuit activity of NTS neurons by codeine, resulting in suppression of cough reflex.