Release of ATP and glutamate in the nucleus tractus solitarii mediate pulmonary stretch receptor (Breuer–Hering) reflex pathway

Alexander V Gourine,Robert Huckstepp,Faming Tian,Nicholas Dale,K Michael Spyer,Enrique Llaudet,Alla Korsak

doi:10.1113/jphysiol.2008.154567

Alexander V Gourine, Robert Huckstepp + Show 5 more

Open Access

https://doi.org/10.1113/jphysiol.2008.154567

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Abstract

The Breuer–Hering inflation reflex is initiated by activation of the slowly adapting pulmonary stretch receptor afferents (SARs), which monosynaptically activate second-order relay neurones in the dorsal medullary nucleus of the solitary tract (NTS). Here we demonstrate that during lung inflation SARs release both ATP and glutamate from their central terminals to activate these NTS neurones. In anaesthetized and artificially ventilated rats, ATP- and glutamate-selective microelectrode biosensors placed in the NTS detected rhythmic release of both transmitters phase-locked to lung inflation. This release of ATP and glutamate was independent of the centrally generated respiratory rhythm and could be reversibly abolished during the blockade of the afferent transmission in the vagus nerve by topical application of local anaesthetic. Microionophoretic application of ATP increased the activity of all tested NTS second-order relay neurones which receive monosynaptic inputs from the SARs. Unilateral microinjection of ATP into the NTS site where pulmonary stretch receptor afferents terminate produced central apnoea, mimicking the effect of lung inflation. Application of P2 and glutamate receptor antagonists (pyridoxal-5′-phosphate-6-azophenyl-2′,4′-disulphonic acid, suramin and kynurenic acid) significantly decreased baseline lung inflation-induced firing of the second-order relay neurones. These data demonstrate that ATP and glutamate are released in the NTS from the central terminals of the lung stretch receptor afferents, activate the second-order relay neurones and hence mediate the key respiratory reflex — the Breuer—Hering inflation reflex.

Highlights

Application of P2 and glutamate receptor antagonists significantly decreased baseline lung inflation-induced firing of the second-order relay neurones. These data demonstrate that ATP and glutamate are released in the nucleus of the solitary tract (NTS) from the central terminals of the lung stretch receptor afferents, activate the second-order relay neurones and mediate the key respiratory reflex – the Breuer–Hering inflation reflex. (Received 27 March 2008; accepted after revision 26 June 2008; first published online 10 July 2008) Corresponding author A
ATP microelectrode biosensors placed into the area of the NTS where stretch receptor afferents (SARs) terminate (Fig. 1C) detected a rhythmic signal that was phase locked to changes in tracheal pressure (Fig. 2A and B)
This signal had a mean amplitude of 11.7 ± 1.3 pA (n = 10). No such rhythmic signal was detected by the ‘null’ sensors that lacked enzymes in the polymer coating or by the ATP biosensors placed outside this circumscribed area (Fig. 2C)

Summary

Introduction

These data demonstrate that ATP and glutamate are released in the NTS from the central terminals of the lung stretch receptor afferents, activate the second-order relay neurones and mediate the key respiratory reflex – the Breuer–Hering inflation reflex.

Results

Conclusion