Distinct cardiopulmonary reflexes evoked by inhaled stimuli

Activation of airway sensory nerves causes respiratory and autonomic reflexes. Most airway sensory afferents are sensitive to noxious stimuli, such as inflammation, irritants, and pollutants. Activation of these nociceptive afferents evokes protective mechanisms such as apnea, cough, and bradycardia. These reflexes may contribute to disease morbidity when excessively activated. Airway nociceptors, largely projecting from the vagal ganglia (nodose and jugular ganglion), are heterogeneous with respect to gene expression and neuroanatomy; our objective is to characterize the reflexes evoked by activation of specific afferent subsets using chemogenetics. To selectively activate vagal afferent subpopulations in vivo, mice were exposed to nebulized clozapine-N-oxide (CNO, selective agonist for the designer receptor exclusively activated by designer drug (DREADD) stimulatory receptor hM3Dq). hM3Dq expression by ROSA26-loxP-STOP-loxP mice was selectively expressed in sensory subpopulations by breeding with Cre recombinase-expressing mice: TRPV1-Cre (all nociceptors), Tac1-Cre (peptidergic/jugular-originating nerves), and P2X2-Cre (nodose-originating nerves). ECGs were recorded via radiotelemetry, and respiration was measured via whole-body plethysmography. CNO inhalation in TRPV1-hM3Dq mice and P2X2-hM3Dq mice (but not control hM3Dq mice) evoked bradypnea and bradycardia. Body temperature decreased after the onset of bradycardia. CNO inhalation in Tac1-hM3Dq mice evoked bradycardia and an increase in minute ventilation without a significant change in respiratory rate. We also used an intersectional approach to express hM3Dq in select afferent populations defined by two genes (e.g. TRPV1+ and P2X2+) using TRPV1-flp mice and the above Cre mice combined with bilateral vagal injections of an AAV delivering dual recombinase-dependent DREADD constructs. CNO inhalation in TRPV1-flp-P2X2-cre-hM3Dq mice and in TRPV1-flp-Tac1-cre-hM3Dq mice both evoked bradypnea and bradycardia. However the bradypnea was accompanied by an increase in inspiratory duration in the TRPV1-flp-Tac1-cre-hM3Dq mice which was absent in the TRPV1-flp-P2X2-cre-hM3Dq mice. These data suggest that chemogenetic activation of Tac1+ afferents can evoke distinct reflexes to P2X2+ afferents, but this may involve afferent subsets other than vagal TRPV1+ populations. NIH T32: 5T32HL160529-03 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.