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

Abstract

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-Bötzinger complex. Methods Studies were performed in 40 young and 55 adult artificially ventilated, decerebrate rabbits. We identified an area in the parabrachial nucleus where α-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 μ-opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (100 μM) into the “tachypneic area” determined the effect of maximal μ-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-Bötzinger complex. Conclusions The “tachypneic area” of the parabrachial nucleus is highly sensitive to μ-opioid receptor activation and mediates part of the respiratory rate depression by clinically relevant administration of opioids.

Differential impact of two critical respiratory centres in opioid‐induced respiratory depression in awake mice

“…; Miller et al . ). One concern and a potential source of conflicting experimental outcomes is that it is unknown if the above described effects were due to activation of somatodendritic or presynaptic receptors in the local area, with one exception (Montandon et al .…”

“…; Miller et al . ). An alternative explanation is that remaining MORs in either region from partial knockout are sufficient to induce the residual respiratory depression.…”

Solving the Opioid Crisis

“…Several key brainstem centers (Fig 1) are sensitive to opioid ligands and can potentially depress breathing, depending on the dosage, type of opioid drugs, and species studied. Opioid inhibition of the pre-Bötzinger complex, 10 the medullary raphe, 11 the Kolliker-Fuse, 12 and the parabrachial nucleus 13 can contribute to respiratory depression by opioid ligands, but their precise contributions need to be clarified. 14 The roles of the neural circuits regulating breathing in respiratory depression is even more complex, considering that opioids may inhibit circuits that can indirectly modulate breathing.…”

Neural basis of opioid-induced respiratory depression and its rescue

“…Recent studies have suggested the involvement of these two brain regions on OIRD pathogenesis by using either pharmacological or genetic approaches. Direct infusion of opioid agonists or antagonists into these brain areas induces or attenuates OIRD (9,12,29,30). Region-specific genetic deletion of the Oprm1 genes by viral delivery of Cre-recombinase into these areas of the Oprm1-floxed mice also attenuates OIRD (13,14).…”

“…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).…”