The Pontine Respiratory Group (PRG) Partially Mediates Clinical Opioid‐Induced Respiratory Depression in Adult Rabbits

Abstract

Recent studies in adult dogs suggest that the parabrachial nucleus, a part of the PRG, plays an important role in the respiratory depression by clinical concentrations of intravenous (IV) opioids (Prkic et al 2012). This study investigated whether a similar area could be identified in adult rabbits. Each rabbit (2.2 – 4.0 kg) was anesthetized with 1‐1.5 MAC sevoflurane, tracheotomized, ventilated and decerebrated. The PRG was functionally identified by microinjecting 70 nl of 50 µM AMPA in a grid‐wise fashion with a glass multi‐barrel electrode from 1‐3 mm caudal of the inferior colliculi and 1‐4 mm lateral of midline into the dorso‐ventral center of neuronal activity. The area of maximal tachypnea as determined from the phrenic neurogram was on average 0.6 mm caudal/2.7 mm lateral/7.2 mm from the dorsal surface (n=24). Bilateral microinjection of the mu‐opioid agonist [D‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO, 100 µM, 700nl) into this region led to a significant decrease in breathing frequency (‐45±9% ; P < 0.001; n=10) via increased expiratory duration (TE= 343±43%; P < 0.001; n=10). This was completely reversed (P > 0.05; n=8) by local microinjection of the opioid‐antagonist naloxone (1mM, 840 nl). In a separate set of animals, bilateral local injection of naloxone into the same area partially reversed the bradypnea caused by systemic opiate administration (0.5 mcg/kg/min IV remifentanil) by attenuating the opiate induced increase in expiration duration (ΔTE= ‐127%; P < 0.05; n=11). These studies suggest that in adult rabbits, PRG mu‐opioid receptors contribute to the bradypnea induced by systemically administered opioids at clinically relevant doses through an increase in expiratory duration.Supported by VA grant I01BX000721.