A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits

Background: The efficacy of opioid administration to reduce postoperative pain is limited by respiratory depression. We investigated whether clinically relevant opioid concentrations altered the respiratory pattern in the parabrachial nucleus, a pontine region contributing to respiratory pattern generation, and compared these effects with a medullary respiratory site, the pre-Botzinger complex. Methods: Studies were performed in 40 young and 55 adult artificially ventilated, decerebrate rabbits. We identified an area in the parabrachial nucleus where alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid microinjections elicited tachypnea. Two protocols were performed in separate sets of animals. First, bilateral microinjections of the mu-opioid receptor agonist [D-Ala, 2 N-MePhe, 4 Gly-ol]-enkephalin (100 mu M) into the tachypneic area determined the effect of maximal mu-opioid receptor activation. Second, respiratory rate was decreased with continuous IV infusions of remifentanil. The opioid antagonist naloxone (1 mM) was then microinjected bilaterally into the tachypneic area of the parabrachial nucleus to determine whether the respiratory rate depression could be locally reversed. Results: Average respiratory rate was 27 +/- 10 breaths/min. First, [D-Ala, 2 N-MePhe, 4 Gly-ol]-enkephalin injections decreased respiratory rate by 62 +/- 20% in young and 45 +/- 26% in adult rabbits (both P < 0.001). Second, during IV remifentanil infusion, bilateral naloxone injections into the tachypneic area of the parabrachial nucleus reversed respiratory rate depression from 55 +/- 9% to 20 +/- 14% in young and from 46 +/- 20% to 18 +/- 27% in adult rabbits (both P < 0.001). The effects of bilateral [D-Ala, 2 N-MePhe, 4 Gly-ol]-enkephalin injection and IV remifentanil on respiratory phase duration in the tachypneic area of the parabrachial nucleus was significantly different from the pre-Botzinger complex. Conclusions: The tachypneic area of the parabrachial nucleus is highly sensitive to mu-opioid receptor activation and mediates part of the respiratory rate depression by clinically relevant administration of opioids.