Naloxone Injections into the Parabrachial Nucleus/ Kölliker‐Fuse Complex, the preBötzinger Complex and the Caudal Medullary Raphe Reverse Remifentanil‐Induced Respiratory Depression

Abstract

Background We have shown that naloxone microinjections into the Parabrachial Nucleus/ Kölliker-Fuse (PBN/KF) complex and the preBötzinger Complex (preBC) partially reversed remifentanil-induced respiratory rate depression (1). The magnitude of reversal was dose dependent. The goal of this study was to determine whether additional naloxone injection into the caudal medullary raphe (CMR (2)) could completely reverse the opioid effect. Methods The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the c5 rootlet, time averaged and used to calculate inspiratory and expiratory duration and peak phrenic activity (PPA). Gridwise localized pressure microinjections of AMPA (50 μM, 70 nl) with a multibarrel glass pipette were used to functionally identify the PBN/KF and preBC. The CMR was defined as the area between 2.0mm caudal and 1.5mm rostral to preBC in the midline. We then injected an “apneic” remifentanil IV bolus (12±2mcg), which interrupted inspiratory activity for at least 60 sec. Next, a remifentanil infusion was started at an “analgesic” dose-rate, defined to achieve respiratory rate depression of 50% of control. At steady-state, we sequentially injected naloxone (1mM, 700nl) into the bilateral PBN/KF, the preBC, and the CMR. We repeated the “apneic” remifentanil bolus after naloxone injection into each area. To determine whether injection order affected the naloxone reversal, in separate sets of animals we microinjected naloxone in the reverse order, or solely into the preBC and CMR. Drug effects were compared with Paired t-tests. Results Figure 1 illustrates the effects of sequential naloxone microinjection into the bilateral PBN/KF, preBC, and CMR. At the end of the naloxone injection sequence, respiratory rate depression was completely reversed (A+B) or even increased above baseline (C). Depression of PPA was completely reversed (p=0.756). Conclusion Naloxone injection into the CMR reversed remifentanil-induced respiratory depression in addition to the reversal achieved in the PBN/KF and preBC at “analgesic” and “apneic” remifentanil doses. Further research is needed to determine whether the naloxone effect in the CMR was partially due to reversal of endogenous opioid-receptor activation (see Palkovic B, Endogenous Opioid-Receptor Activation in the Caudal Medullary Raphe Depresses Respiratory Rate in Decerebrate Rabbits, EB 2021). (1) Palkovic et al., Anesthesiology 2020, A3038 (2) Zhang et al., Anesthesiology 2007, 107: 288-97