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

Abstract

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). Local application of the NK1 agonist [SAR9,Met (O2)11]‐SP (SPNK1) 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. Under current clamp, SPNK1 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. Under voltage clamp, SPNK1 evoked an inward current and increased input resistance, but had no effect on inspiratory synaptic currents. SPNK1 currents persisted in the presence of TTX, were GR82334 sensitive, were reduced with hyperpolarization and reversed near the expected EK. Effects of the α1‐noradrenergic receptor agonist phenylephrine (PE) on repetitive firing behaviour were virtually identical to those of SPNK1. Moreover, SPNK1 currents were completely occluded by PE, suggesting that common intracellular pathways mediate the actions of NK1 and α1‐noradrenergic receptors. In spite of the similar actions of SPNK1 and PE on XII MN responses to somally injected current, α1‐noradrenergic receptor activation potentiated inspiratory synaptic currents and was more than twice as effective in potentiating XII nerve inspiratory burst amplitude. 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 SPNK1‐sensitive inspiratory XII MNs, support the endogenous modulation of XII MN excitability by SP. 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 SPNK1. In conclusion, SPNK1 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.

Substance P-Mediated Modulation of Pacemaker Properties in the Mammalian Respiratory Network

“…Previous reports have shown that SP depolarizes respiratory neurons (Gray et al, 1999;Shvarev et al, 2002Shvarev et al, , 2003 and respiratory-related phrenic and hypoglossal motoneurons (Ptak et al, 1999(Ptak et al, , 2000Yasuda et al, 2001). Here, we demonstrate that this depolarization was not specific to a subpopulation of inspiratory PBC neurons.…”

“…SP activates voltage-dependent Ca 2ϩ channels, voltage-dependent K ϩ conductances, Cl Ϫ currents, Ih currents, voltage-dependent Na ϩ channels, and nonselective cationic channels (Adams et al, 1983;Stanfield et al, 1985;Bley and Tsien, 1990;Shen and North, 1992;Bertrand and Galligan, 1994;Aosaki and Kawaguchi, 1996). In most neurons, SP depolarizes membrane potential by decreasing resting K ϩ conductances (Akasu et al, 1996;Lepre et al, 1996;Ptak et al, 2000;Yasuda et al, 2001). This seems not to be the case for respiratory neurons because the slow depolarization persisted after blocking K ϩ channels with TEA externally or cesium internally.…”

Identified Motoneurons Involved in Sexual and Eliminative Functions in the Rat Are Powerfully Excited by Vasopressin and Tachykinins

“…In neonatal lumbar motoneurons, the substance P-evoked depolarization was attributable to the suppression of a Ba ϩ -sensitive K ϩ conductance (Fisher and Nistri, 1993). In phrenic motoneurons and in hypoglossal motoneurons, NK1 receptor activation induced membrane depolarization, or evoked an inward current, by inhibiting a resting K ϩ current (Ptak et al, 2000;Yasuda et al, 2001). In hypoglossal motoneurons, this excitatory effect was at least in part mediated by the two-pore domain K ϩ channel TASK-1 (TWIK-related acid-sensitive K ϩ channels) (Talley et al, 2000).…”

“…In contrast, NK2 and NK3 receptor agonists were ineffective in eliciting any direct response. It has been reported by others that tachykinins can induce depolarization or generate an inward current in nonpudendal spinal motoneurons or in brainstem motoneurons (Konishi and Otsuka, 1974;Otsuka and Yanagisawa, 1980;Fisher and Nistri, 1993;Fisher et al, 1994;Ptak et al, 2000;Yasuda et al, 2001).…”

Neurokinin Receptor-Expressing Pre-Bötzinger Complex Neurons in Neonatal Mice Studied In Vitro

“…SP increases excitability through the closure of K ϩ channels in hypoglossal motoneurons (Yasuda et al 2001) and C1 neurons that are situated at the ventral border of the preBötC (Blessing 1997;Li and Guyenet 1997). Our data set did not contain C1 neurons because I SP never reversed at E K and was unaffected by intracellular and extracellular K ϩ channel blockers.…”