Hypoxia and hypercapnia have little impact on remifentanil-induced changes in respiratory phase timing and neuronal activity in the preBötzinger complex in adult rabbits

Background: We have previously shown that respiratory depression from intravenous (IV) remifentanil could be partially reversed with naloxone injection into the preBötzinger complex (preBötC) during moderate hypercapnia (PCO2 50 mmHg). We also showed that PCO2 significantly affected phase timing and neuronal discharge frequency ( Fn ) between PCO2 30-50 mmHg, but that there was little additional effect above ~50 mmHg. This study investigated the effects of “analgesic” remifentanil concentrations on Fn of individual preBötC neurons and whether an increase in chemodrive, i.e., hypercapnia and hypoxia, reversed the remifentanil effect on phase timing and Fn. Methods: The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4 kg) of either sex were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the C5 rootlet, time averaged and used to calculate inspiratory (TI) and expiratory durations (TE) and peak phrenic activity (PPA). We extracellularly recorded individual neurons in the functionally identified preBötC using multichannel electrodes (Neuronexus, Ann Arbor, MI). Fn was continuously displayed and recorded and averaged posthoc using cycle-triggered histograms (30-40 cycles, Spike2, CED, Cambridge, MA). Neurons were identified at PCO2 50 mmHg. Remifentanil was infused IV to achieve a steady-state 50% depression in respiratory rate and continued until the end of the protocol. Parameters were sampled at PCO2 50 mmHg, PCO2 50mmHg with remifentanil, PCO2 60mmHg with remifentanil, and PCO2 60 mmHg with hypoxia (hyp, FiO2 0.15) with remifentanil. Complete reversal was achieved with IV naloxone. Statistical analysis with Mann-Whitney-U test for differences between states, values are median (25-75% range), p<0.05. Results: In 17 animals, remifentanil increased TI from 0.8 (0.7-0.9) sec to 1.3 (1.1-1.4) sec (p<0.05) and TE from 0.8 (0.6-0.9) sec to 1.9 (1.5-2.2) sec (p<0.05). PPA did not change significantly. Additional hypercapnia and hypoxia did not reverse the effect on TI and TE, however, hypoxia increased PPA (p<0.05). Remifentanil significantly decreased the Fn of inspiratory augmenting neurons from 56.7 (31.8-76.1) Hz to 40.4 (23.6-67.4) Hz (n=62, p<0.05) and inspiratory parabolic neurons from 29.4 (19.3-50.0) Hz to 14.9 (9.2-28.3) Hz (n=18, p<0.05). Hypercapnia and hypoxia did not alter that effect. The effect of remifentanil on inspiratory (n=10) and expiratory decrementing (n=6) neurons was not statistically significant, and there was again no effect of additional hypercapnia and hypoxia. Conclusion: Although hypercapnia and hypoxia increase chemodrive to the respiratory rhythm generator and have substantial effects on phase timing and tidal volume in normoxic, normocapnic individuals, the effect during remifentanil-induced respiratory depression is very limited. This matches the lack of effect on individual respiratory neuronal discharge. The increase in PPA during hypoxia may be due to a direct effect on respiratory premotor and motoneurons. The results reflect the clinical experience that even the significant hypercapnia and hypoxia that is experienced by victims of opioid overdose does not overcome the respiratory depression, leading to death. It is important to test whether similar limitations exist for respiratory stimulant drugs. NIH R01-HL159546 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.