Distinct cardiopulmonary reflexes evoked by stimuli given intravenously

Activated vagal afferents evoke cardiopulmonary reflexes via the modulation of medullary networks. However, the link between genetically- and anatomically-distinct nociceptive vagal subsets and function is poorly understood. We hypothesize that specific reflexes are evoked by specific nociceptive subsets due to their central termination and neurotransmitter content. Previously, we had shown that cardiopulmonary reflexes evoked by irritants given by inhalation or intravenously were differentially sensitive to anesthetics, suggesting mechanistic differences. The objective here is to identify the mechanisms and pathways necessary for the modulation of respiratory rate and heart rate by airway nociceptor subsets activated by intravenously applied stimuli. We used chemogenetics to selectively activate genetically-identified vagal afferent subsets. The stimulatory DREADD receptor hM3Dq was expressed either from the ROSA26-Lox-STOP-Lox locus (R26-hM3Dq) or from recombinase-sensitive adeno-associated viruses (AAV) injected bilaterally into the vagal ganglia. For this study we used P2X2-cre as a marker of nodose neurons, Tac1-cre as a marker of peptidergic neurons, and TRPV1-cre or TRPV1-Flp as a marker of nociceptive neurons. In ketamine/dexamethasone-anesthetized mice, we measured heart rate with surface ECG and breathing rate with diaphragmatic EMG in response to 20ml i.v. injection (via jugular vein) of vehicle and the selective DREADD agonist CNO (3 to 300mg/ml). Intravenous CNO had no effect on control mice. Whereas intravenous CNO evoked bradycardia and bradypnea in P2X2-Cre-R26-hM3Dq mice (P2X2+ afferents) and TRPV1-Cre-AAV-flex-hM3Dq mice (TRPV1+ vagal afferents), but evoked tachypnea and tachycardia in Tac1-Cre-R26-hM3Dq mice (Tac1+ afferents). Intravenous CNO evoked bradypnea in TRPV1-flp-Tac1-Cre-AAV-ConFon-hM3Dq mice (TRPV1+Tac1+ vagal afferents) but evoked tachypnea in Tac1-Cre-AAV-ConFoff-hM3Dq mice (Tac1+TRPV1-negative vagal afferents). These data suggest that multiple vagal afferent pathways are activated by stimuli within the pulmonary circulation and that these pathways can evoke dramatically distinct responses. RO1HL152219 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.