Reflex regulation of respiration and heart rate by inhaled activators of vagal bronchopulmonary afferents

Activation of airway sensory afferent nerves causes respiratory and autonomic reflexes. Most airway afferents are activated by noxious stimuli, such as inflammation, irritants, and pollutants. Activation evokes protective reflexes such as cough, bronchospasm, and changes in respiration and cardiovascular function. Airway nociceptors, projecting from the vagal ganglia (nodose and jugular ganglion), are heterogeneous with respect to gene expression and neuroanatomy. Here, we have characterized the cardiorespiratory reflexes in conscious mice evoked by activation of specific afferent subsets by inhaled stimuli. Capsaicin (TRPV1 agonist) and allyl isothiocyanate (AITC, TRPA1 agonist) evoked bradypnea associated with increased tidal volume and increased time of inspiration (<i>T</i>_I), expiration (<i>T</i>_E), and respiratory pause (<i>T</i>_P). AITC evoked greater bradycardia than capsaicin. AITC-evoked bradycardia was abolished by muscarinic inhibitor atropine, implicating a parasympathetic-mediated reflex. We expressed the chemogenetic hM3Dq DREADD receptor under the control of TRPV1^Cre (nociceptive), TRPV1^Flp (nociceptive), P2X2^Cre (nodose), or Tac1^cre (peptidergic) genes using various combinations of mouse models and intraganglionic injections of adeno-associated viral vectors. hM3Dq-expressing airway afferents were activated by inhalation of clozapine-<i>N</i>-oxide (CNO). CNO activation of TRPV1⁺ afferents evoked bradycardia and bradypnea, associated with increased <i>T</i>_I, <i>T</i>_E, and <i>T</i>_P. CNO activation of P2X2⁺ and vagal P2X2⁺TRPV1⁺ afferents evoked bradycardia and bradypnea, associated with increased <i>T</i>_P. CNO activation of Tac1⁺ afferents evoked bradycardia, whereas activation of vagal Tac1⁺TRPV1⁺ afferents evoked bradycardia and bradypnea, associated with increased <i>T</i>_E but not increased <i>T</i>_P. Our data suggest that multiple functionally distinct subsets of vagal nociceptors innervate the airways that can differentially regulate cardiorespiratory function.<b>NEW & NOTEWORTHY</b> This study uses intersectional chemogenetics, radiotelemetry, and whole body plethysmography to determine the effect of selective stimulation of distinct sensory nerve subsets on cardiorespiratory function in awake mice. We show that TRPA1⁺ afferents evoke greater reflex bradycardia than TRPV1⁺ afferents. We show that P2X2⁺ (nodose) afferents induce bradypnea through an increased time of pause, whereas Tac1⁺TRPV1⁺ (jugular nociceptive) afferents induce bradypnea through prolongation of expiration. Thus, distinct afferent subsets can differentially regulate cardiorespiratory function.