Role of central neurotransmission and chemoreception on airway control

Abstract

This review summarizes work on central neurotransmission, chemoreception and CNS control of cholinergic outflow to the airways. First, we describe the neural transmission of bronchoconstrictive signals from airway afferents to the airway-related vagal preganglionic neurons (AVPNs) via the nucleus of the solitary tract (nTS) and, second, we characterize evidence for a modulatory effect of excitatory glutamatergic, and inhibitory GABAergic, noradrenergic and serotonergic pathways on AVPN output. Excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second order neurons within the nTS, via a glutamate-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor signaling pathway. These nTS neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command through descending fibers and airway intramural ganglia to airway smooth muscle, submucosal secretory glands, and the vasculature. The strength and duration of this reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs. In addition, central noradrenergic and serotonergic inhibitory pathways appear to participate in the regulation of cholinergic drive to the tracheobronchial system. Down-regulation of these inhibitory influences results in a shift from inhibitory to excitatory drive, which may lead to increased excitability of AVPNs, heightened airway responsiveness, greater cholinergic outflow to the airways and consequently bronchoconstriction. In summary, centrally coordinated control of airway tone and respiratory drive serve to optimize gas exchange and work of breathing under normal homeostatic conditions. Greater understanding of this process should enhance our understanding of its disruption under pathophysiologic states.

Figure 1

Reflex-induced glutamate release within the nucleus tractus solitarius (nTS). (A) Average concentrations (mean ± SEM; pg/μL) of L-glutamate (Glu) in a control state (baseline), during excitation of bronchopulmonary sensory receptors (stimulation), and in a post-stimulation period (recovery). Filled bars: ferrets with intact innervation of the airways and lungs (vagus intact; n = 5). Open bars: ferrets after afferent and efferent denervation of the airways and lungs (vagotomized and superior laryngeal nerves cut; n = 3). (B) Tracheal smooth muscle tone measured as pressure in a bypassed tracheal segment (PTseg, cmH₂O) before, during, and after stimulation in ferrets with intact innervation of the airways. Stimulation of afferent sensory fibers significantly increased glutamate release and subsequently augmented pressure in the tracheal segment.* = p < 0.05. (Modified from Haxhiu et al., 2000a).

Figure 2

(A) An example of the effect of chemical stimulation of the ventrolateral periaqueductal gray (vl PAG) cell group by microinjection of L-glutamate (4 nmol) on tracheal segment pressure (PTseg, cmH₂O) in a paralyzed and mechanically ventilated ferret. (B) Average results (mean ± SEM; n = 6) of GABA obtained from microdialysates collected from the airway-related vagal preganglionic neurons (AVPNs) within the rostral ventrolateral medulla in a control state (Baseline) and after vl PAG stimulation (PAG stim). (C) Average data (mean ± SEM; n = 9) on the effect of vl PAG stimulation on tracheal smooth muscle tone in response to L-glutamate-induced activation of vl PAG before and after bicuculline microperfusion into the AVPN region of paralyzed and oxygen-ventilated ferrets. Stimulation of vl PAG significantly increased GABA release within the AVPN region which decreased in tracheal pressure. This response was abolished following bilateral microperfusion of bicuculline into the AVPN region. * = p <0.05 (Modified, from Haxhiu et al., 2002).

Figure 3

Effects of endogenous norepinephrine release on cholinergic outflow to the airways in ferrets. (A) Average norepinephrine levels (mean ± SEM; fg/ml; n = 8) obtained from microdialysates collected from airway-related vagal preganglionic motor neurons (AVPNs) within the rostral nucleus ambiguus (rNA) in a control state and at different time points after cessation of chemical stimulation of locus coeruleus (LC) neurons (horizontal bar). In three control animals, no stimulation was performed. (B) Tracings of tracheal segment pressure (PTseg, cmH₂O) from a paralyzed and oxygen-ventilated ferret. In a control period (A), activation of LC neurons by L-glutamate (4 nmol/80 nl) induced a decrease in tracheal tone, expressed as a decrease of PTseg. Bilateral microperfusion of yohimbine into the rostral nucleus ambiguus (rNA) region diminished the tracheal smooth muscle response to LC stimulation. (C) Average decrease in PTseg (mean ± SEM; PTseg, cmH₂O; n = 8) induced by LC stimulation before (A) and after (B) microperfusion of α2A-adrenoreceptor blocker into the rNA regions. Microperfusion of α2A-adrenoreceptor blocker inhibited the decreases in tracheal pressure to LC stimulation. * = p < 0.05. (Modified from Haxhiu et al., 2003a).

Figure 4

(A) An example of the effect of raphe neuron stimulation (L-glutamate, 4 nmol/80 nl) on serotonin release (μmol) in the rostral nucleus ambiguus (rNA) of an anesthetized cat. (B) The medullary raphe stimulation-induced changes (mean ± SEM; PTseg, cmH₂O) in tracheal tone (Δ PTseg) and lung resistance (Δ RL; cmH₂O/L/s) in a control period, and after 5-HT receptor blockade with topical application of methysergide (100 mg/site), a broad-spectrum serotonin receptor antagonist. Release of serotonin decreased airway smooth muscle tone and lung resistance (p < 0.05). This response was diminished after blockade of 5-HT receptors within the ventrolateral medulla (Modified, from Haxhiu et al., 1998).