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The mode of action of L-DOPA on excitatory synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS) was studied using the rat brainstem slices. Superfusion of L-DOPA (10 μM) reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without any effect on the amplitude. A low concentration (1 μM) was ineffective on the mEPSCs, and the highest concentration (100 μM) exerted a stronger inhibitory effect. L-DOPA (10 μM) decreased the amplitude of EPSCs (eEPSCs) evoked by electrical stimulation of the tractus solitarius and increased the paired-pulse ratio. The inhibitory effects of L-DOPA on mEPSCs and eEPSCs were similar to those of dopamine (100 μM). The effects of L-DOPA were blocked by a competitive antagonist, L-DOPA methyl ester (100 μM) and also by a D 2 receptor antagonist, sulpiride (10 μM), while those of dopamine were blocked by the latter but not by the former. In reserpine (5 mg/kg, s.c.)-treated rats, the effects of L-DOPA on both mEPSCs and eEPSCs were completely abolished, but those of dopamine remained unchanged. The present results suggest a possibility that L-DOPA may induce the release of dopamine from the axon terminals in the NTS and the released dopamine suppresses the glutamatergic transmission through activation of the presynaptic D 2 receptors. [ABSTRACT FROM AUTHOR]

This study was carried out on decerebrate, paralyzed and artificially ventilated cats to investigate the central regulatory mechanism for cough reflex. Fictive cough was induced by repetitive stimulation of the superior laryngeal nerve (SLN) or the nucleus tractus solitarius (NTS), and characterized by an increased inspiratory discharge in the phrenic nerve (stage 1 of cough; S1C) and large burst discharge in the iliohypogastric nerve (stage 2 of cough; S2C). Membrane potential was recorded from the neurons located in the cough-inducible sites of the NTS. Seven augmenting inspiratory (aug-I), 25 inspiratory-modulated (I-mod) and 16 non-respiratory (non-R) neurons were encountered, all of which showed short-latency (7.5 ± 1.6 ms, n = 48) waves of excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) in response to single pulse stimulation of the SLN. Out of these, all 7 aug-I and 12 I-mod neurons depolarized during the S1C and hyperpolarized during the S2C (DH-type response). Three I-mod and five non-R neurons showed membrane hyperpolarization during both stages (HH-type response). Ten I-mod and three non-R neurons displayed membrane depolarization during the S1C and S2C (DD-type response). The remaining eight non-R neurons showed no response during the fictive cough (NN-type response) but a long-lasting EPSP wave to single SLN stimulation. The NTS neurons recorded here were divided into three groups. Group I neurons with the NN-type response may be the second-order relay neurons. Group II neurons with the DD-type response may integrate the tussigenic afferent information and send a gate signal to the cough pattern generator. Group III neurons with either DH-type or HH-type response may constitute the network of cough pattern generation or modulatory circuits recruited during the cough reflex. The present study suggests that Group II neurons may play a gating role in generating the cough reflex. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Although codeine is the most prominent and centrally acting antitussive agent, the precise sites and mode of its action have not been fully understood yet. In the present study, we examined the effects of codeine on synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS), which is the first central relay site receiving tussigenic afferent fibers, by using whole-cell patch-clamp recordings in guinea-pig brainstem slices. Codeine (0.3–3 mM) significantly decreased the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of the tractus solitarius in a naloxone-reversible and concentration-dependent manner, but it had no effect on the decay time of evoked EPSCs (eEPSCs). The inhibition of eEPSCs was accompanied by an increased paired-pulse ratio of two consecutive eEPSCs. The inward current induced by application of AMPA remained unchanged after codeine application. A voltage-sensitive K+ channel blocker, 4-aminopyridine (4-AP) attenuated the inhibitory effect of codeine on eEPSCs. These results suggest that codeine inhibits excitatory transmission from the primary afferent fibers to the second-order NTS neurons through the opioid receptors that activate the 4-AP sensitive K+ channels located at presynaptic terminals. [Copyright &y& Elsevier]

Abstract: The cytosolic Ca2+ released from internal stores is important for distinctive cell functions. To assess the role of ryanodine/Ca2+ releasing mechanisms in the rhythmic activity of respiratory neurons, effects of intracellular injection of ryanodine on the membrane potential trajectory of postinspiratory and augmenting inspiratory neurons were investigated in unanesthetized, decerebrate, paralyzed and artificially ventilated cats. Ryanodine injection hyperpolarized the membrane and decreased input resistance throughout the respiratory cycle in both types of respiratory neurons. Specifically, membrane repolarization during postinspiration was accelerated in postinspiratory neurons, and the large hyperpolarization at the onset of postinspiration was increased in augmenting inspiratory neurons. Spike-afterhyperpolarization consisting of a fast, early component and slow, late component increased in size after ryanodine, resulting in prolongation of inter-spike intervals and decrease of burst discharge. Intracellular injection of caffeine produced similar effects on these respiratory neurons, and Ruthenium Red, an antagonist of ryanodine receptors, had opposite effects. Immunoreactivity for ryanodine receptors was detected in all respiratory neurons labeled intracellularly with neurobiotin. These results demonstrate that ryanodine-sensitive Ca2+ stores modulate the periodic membrane potential fluctuations and spike activity in respiratory neurons. [Copyright &y& Elsevier]