Substance P and NK1 receptor activation within the ventral medullary respiratory network prolongs expiratory time

P Boscan,Je Smith,Jfr Paton

doi:10.1186/rr147

Abstract

Substance P exerts different effects when applied to the medullary respiratory network. In vivo microinjection of substance P into the ventrolateral medulla prolongs expiratory time and augments tidal volume [1,2] whereas respiratory frequency is enhanced in rhythmic in vitro preparations of immature rat [3,4]. Here, we microinjected substance P and an NK1 receptor agonist (GR73632) into the ventral respiratory group of an arterially perfused, in situ, working heart-brainstem preparation of mature rat[5]. We wished to determine (i) the effects of NK1 receptor activation in the ventral medullary respiratory network of this perfused preparation and (ii), the neuronal mechanism that could account for any changes in respiratory motor outflow. Unilateral microinjection of substance P (1000 pmol) into the ventral respiratory group prolonged phrenic nerve activity cycle length from 2.0 ± 0.2–4.0 ± 0.7 s (P < 0.01; n = 7 sites). Qualitatively a similar response was observed with GR73632 (100 pmol). At these responsive sites, CP-99,994, an NK1 receptor antagonist, failed to affect respiratory motor output. Recordings from the central end of the vagus nerve indicated both inspiratory and post-inspiratory discharge (ie, stageI expiratory activity) in control. Following a microinjection of substance P, post-inspiratory discharge was both augmented and prolonged. Extracellular recordings were made from 23 respiratory neurones using compound microelectrodes for pressure ejection of drugs. Substance P (10 mM) excited 66% of post-inspiratory neurones raising both the peak firing frequency and total number of action potentials per cycle by 15% and 56% respectively; both effects were prevented by antagonising NK1 receptors. Our findings indicate that substance P acting on NK1 receptors in the ventral respiratory network promotes a prolongation of expiratory time via an excitatory effect on some post-inspiratory neurones.

Highlights

To be effective, inspiratory muscles on the left and right sides must contract together
We have found that a prominent gap in the column of ventral respiratory group (VRG) The nucleus tractus solitarii (NTS) relays information from primary related parvalbumin cells [2] likely corresponds to the pBc since visceral receptors to the central nervous system and is critically parvalbumin cells are rare in this zone and never co-localize with involved in the reflex control of autonomic functions
The specific protein(s) necessary for longterm facilitation (LTF) is unknown, we recently found that episodic hypoxia and LTF are associated with elevations in ventral spinal concentrations of brain derived neurotrophic factor (BDNF)

Summary

Introduction

Inspiratory muscles on the left and right sides must contract together. The left and right halves of the diaphragm are synchronised because a bilateral population of medullary premotor neurones [1] simultaneously excites left and right phrenic motoneurones. Transection studies demonstrate that each side of the brainstem is capable of generating respiratory rhythm independently [2], so that left and right medullary inspiratory neurones must themselves be synchronised. The interconnections and common excitation that accomplish such synchronisation are unknown in rats. The respiratory rhythm of hypoglossal (XII) nerve discharge in transverse medullary slice preparations from neonatal rats is thought to originate in the region of the ventral respiratory group (VRG); generated there by a combination of “pacemaker” neurones [1] and their interactions with other respiratory neurones. Our goal was to discover interconnections between left and right VRG neurones as well as their connections to XII motoneurones

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