Activation of μ-opioid receptors differentially affects the preBötzinger Complex and neighbouring regions of the respiratory network in the adult rabbit

Abstract

The role of the different components of the respiratory network in the mediation of opioid-induced respiratory depression is 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) in anesthetized, vagotomized, paralyzed and artificially ventilated adult rabbits making use of bilateral microinjections (30−50 nl) of the μ-opioid receptor agonist [D-Ala 2 , N-Me-Phe 4 , Gly 5-ol]-enkephalin (DAMGO). Dosedependent effects were observed. In the preBötC and the BötC 0.1 mM DAMGO microinjections caused mainly reductions in peak phrenic amplitude associated with tonic phrenic activity and irregular (ataxic) patterns of breathing that were more pronounced in the preBötC. Apneic effects developed at 0.5 mM. In the iVRG DAMGO provoked decreases in amplitude and frequency of phrenic bursts at 0.1 mM and apnea at 0.5 mM. Local 5 mM naloxone reversed the apneic effects. The results imply that different components of the respiratory network may contribute to opioid-induced respiratory disorders.

Neural basis of opioid-induced respiratory depression and its rescue

“…In comparison, we exploited the Oprm1 Cre mouse line which provides access to a restricted neuronal population, and obtained multi-faceted evidence supporting the role of the parabrachial nucleus in OIRD. In our view, OIRD is a synergistic outcome from impairment of the interconnected pontomedullary breathing network that widely expresses MOR both pre-and post-synaptically (10,11,30,44,45). For example, parabrachial neurons send tonic excitatory inputs to the preBötC (39,43,46,47), and both of these areas express MOR (18,48).…”

“…They should localize to the breathing control network and express the µ-opioid receptor (MOR, encoded by the Oprm1 gene), which has been demonstrated as the primary mediator of both the analgesic and respiratory effects of opioids (7,8). Two candidate structures satisfy these criteria, namely the pre-Bötzinger complex (preBötC) and the parabrachial complex (9)(10)(11)(12)(13)(14)(15)(16)(17). The former lies in the ventrolateral medulla and is the primary generator of the respiratory rhythm (18)(19)(20).…”

Neural mechanisms underlying respiratory regulation within the preBötzinger complex of the rabbit

“…NA, nucleus ambiguus; NOI, nucleus olivaris inferior; NTS, nucleus tractus solitarii; NV, nucleus tractus spinalis nervi trigemini; P, tractus pyramidalis. Modified from Mutolo et al (2002) and Cinelli et al (2020). microinjections caused increases in respiratory frequency and decreases in peak phrenic amplitude (Fig.…”

“…1C and Fig. 2D; see Mutolo et al, 2002Mutolo et al, , 2005Bongianni et al, 2008Bongianni et al, , 2010Iovino et al, 2019;Cinelli et al, 2020). Experiments were performed on α-chloralose-urethane anaesthetized, vagotomized, paralyzed and artificially ventilated rabbits.…”

“…Respiratory variables, i.e. respiratory frequency (breaths/min), the inspiratory (T I ) and expiratory (T E ) duration, as well as the peak amplitude of the rectified, integrated phrenic nerve activity (measured in arbitrary units, normalized to control), were measured in the period immediately preceding each trial, at the time when the maximum response to drug microinjections occurred and during the recovery period (see Mutolo et al, 2002Mutolo et al, , 2005Bongianni et al, 2008Bongianni et al, , 2010Pantaleo et al, 2011;Iovino et al, 2019;Cinelli et al, 2020). The respiratory effects observed in response to microinjections of several neuroactive agents into this region allowed us to characterize the rabbit preBötC.…”