Differential Respiratory Effects of µ‐opioid Receptor Activation within the preBötzinger Complex and Neighbouring Respiration‐related Regions in the Rabbit

Abstract

It is well known that opioids induce respiratory depression by activating µ-opioid receptors (MORs). Although MORs are expressed throughout the entire brainstem respiratory network, the effects of their activation within the different respiration-related regions are still unclear. We investigated the contribution of the preBötzinger Complex (preBötC) and the neighbouring Bötzinger Complex (BötC) and inspiratory portion of the ventral respiratory group (iVRG) to the MOR-induced respiratory depression in anesthetized, vagotomized, paralyzed and artificially ventilated adult rabbits making use of microinjections (30-50 nl) of the MOR agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO). Dose-dependent effects were observed. DAMGO microinjected at 0.1 mM into the preBötC and the BötC caused progressive reductions in peak phrenic amplitude associated with tonic phrenic activity and patterns of breathing displaying irregularities that were more marked in the preBötC (ataxic breathing). Increases or no changes in respiratory frequency accompanied these responses in the preBötC and the BötC, respectively. Tonic apneic effects developed at 0.5 mM. DAMGO microinjected into the iVRG provoked decreases in the amplitude and frequency of phrenic bursts at 0.1 mM and apnea at 0.5 mM. DAMGO-induced increases in the variability of peak phrenic amplitude and time components of the breathing pattern were more pronounced after microinjections into the preBötC. Local application of 5 mM naloxone reversed the apneic effects in all instances. The results provide further insides into the role of MORS in the genesis of respiratory depression induced by systemically administered opioids. They suggest that various areas of the respiratory network differentially contribute to the opioid-induced respiratory disorders and support the view that the preBötC may play a prominent role.