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Modulation of hypoglossal motoneuron excitability by NK1 receptor activation in neonatal mice in vitro

Kouichi Yasuda, Dean M. Robinson, Subramaniam R. Selvaratnam, Carmen W. Walsh, Angus J. C. McMorland and Gregory D. Funk

1. The effects of substance P (SP), acting at NK1 receptors, on the excitability and inspiratory activity of hypoglossal (XII) motoneurons (MNs) were investigated using rhythmically active medullary-slice preparations from neonatal mice (postnatal day 0-3).
2. Local application of the NK1 agonist [SAR⁹,Met (O₂)¹¹]-SP (SP_NK1) produced a dose-dependent, spantide- (a non-specific NK receptor antagonist) and GR82334-(an NK1 antagonist) sensitive increase in inspiratory burst amplitude recorded from XII nerves.
3. Under current clamp, SP_NK1 significantly depolarized XII MNs, potentiated repetitive firing responses to injected currents and produced a leftward shift in the firing frequency-current relationships without affecting slope.
4. Under voltage clamp, SP_NK1 evoked an inward current and increased input resistance, but had no effect on inspiratory synaptic currents. SP_NK1 currents persisted in the presence of TTX, were GR82334 sensitive, were reduced with hyperpolarization and reversed near the expected E_K.
5. Effects of the ₁-noradrenergic receptor agonist phenylephrine (PE) on repetitive firing behaviour were virtually identical to those of SP_NK1. Moreover, SP_NK1 currents were completely occluded by PE, suggesting that common intracellular pathways mediate the actions of NK1 and ₁-noradrenergic receptors. In spite of the similar actions of SP_NK1 and PE on XII MN responses to somally injected current, ₁-noradrenergic receptor activation potentiated inspiratory synaptic currents and was more than twice as effective in potentiating XII nerve inspiratory burst amplitude.
6. GR82334 reduced XII nerve inspiratory burst amplitude and generated a small outward current in XII MNs. These observations, together with the first immunohistochemical evidence in the newborn for SP immunopositive terminals in the vicinity of SP_NK1-sensitive inspiratory XII MNs, support the endogenous modulation of XII MN excitability by SP.
7. In contrast to phrenic MNs (Ptak et al. 2000), blocking NMDA receptors with AP5 had no effect on the modulation of XII nerve activity by SP_NK1.
8. In conclusion, SP_NK1 modulates XII motoneuron responses to inspiratory drive primarily through inhibition of a resting, postsynaptic K⁺ leak conductance. The results establish the functional significance of SP in controlling upper airway tone during early postnatal life and indicate differential modulation of motoneurons controlling airway and pump muscles by SP.

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