Rebuttal from Peter M. Lalley, Paul M. Pilowsky, Hubert V. Forster and Edward J. Zuperku

Lalley, Peter M.; Pilowsky, Paul M.; Forster, H. V.; Zuperku, Edward J.

doi:10.1113/jphysiol.2013.268318

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…There are conflicting results regarding the brainstem location where clinically relevant , nanomolar opioid concentrations depress respiratory rate 26–29 . Since the discovery of pacemaker-like, opioid-receptor containing neurons in the preBötC, investigators have focused on this area 30 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…A recently published point-counterpoint debate on this topic highlighted the ongoing controversy and emphasized the clinical relevance of identifying the site of opioid effect. 11–14 …”

Section: Introductionmentioning

confidence: 99%

Opioid-induced Respiratory Depression Is Only Partially Mediated by the preBötzinger Complex in Young and Adult Rabbits In Vivo

et al. 2015

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Background The preBötzinger Complex (preBC) plays an important role in respiratory rhythm generation. This study was designed to determine whether the preBC mediated opioid-induced respiratory rate depression at clinically relevant opioid concentrations in vivo and whether this role was age-dependent. Methods Studies were performed in 22 young and 32 adult New Zealand White rabbits. Animals were anesthetized, mechanically ventilated and decerebrated. The preBC was identified by the tachypneic response to injection of D,L-homoysteic acid. (1) The mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly-ol]-enkephalin (DAMGO, 100μM) was microinjected into the bilateral preBC and reversed with naloxone (1mM) injection into the preBC. (2) Respiratory depression was achieved with intravenous remifentanil (0.08–0.5 mcg/kg/min). Naloxone (1mM) was microinjected into the preBC in an attempt to reverse the respiratory depression. Results (1) DAMGO injection depressed respiratory rate by 6 ± 8 breaths/min in young and adult rabbits (mean ± SD, p <0.001). DAMGO shortened the inspiratory and lengthened the expiratory fraction of the respiratory cycle by 0.24 ± 0.2 in adult and young animals (p <0.001). (2) During intravenous remifentanil infusion, local injection of naloxone into the preBC partially reversed the decrease in inspiratory fraction/increase in expiratory fraction in young and adult animals (0.14 ± 0.14, p <0.001), but not the depression of respiratory rate (p = 0.19). PreBC injections did not affect respiratory drive. In adult rabbits, the contribution of non-preBC inputs to expiratory phase duration was larger than preBC inputs (3.5(−5.2–1.1), median (25%–75%), p = 0.04). Conclusions Systemic opioid effects on respiratory phase timing can be partially reversed in the preBC without reversing the depression of respiratory rate.

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Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone

Wong¹,

Perkins²,

Tressler³

et al. 2017

Inhalation Toxicology

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This study examined the real-time exposure-response effects of aerosolized carfentanil (CRF) on opioid-induced toxicity, respiratory dynamics and cardiac function in mice. Unrestrained, conscious male CD-1 mice (25-30 g) were exposed to 0.4 or 4.0 mg/m of aerosolized CRF for 15 min (Ct = 6 or 60 mg min/m) in a whole-body plethysmograph chamber. Minute volume (MV), core body temperature (T), mean arterial blood pressure (MAP) and heart rate (HR) were evaluated in animals exposed to CRF or sterile HO. Loss of consciousness and Straub tail were observed in before 1 min following initiation of exposure to 6 or 60 mg min/m of CRF. Clinical signs of opioid-induced toxicity were observed in a dose-dependent manner. Exposure to 6 or 60 mg min/m of CRF resulted in significant decrease in MV as compared to the controls. MAP, HR and T decreased 24 h in animals exposed to either 6 or 60 mg min/m of CRF as compared to the controls. Post-exposure administration of naloxone (NX, 0.05 mg/kg, i.m.) did not increase the MV of animals exposed to CRF to control levels within 24 h, but decreased clinical signs of opioid-induced toxicity and the duration of respiratory depression. This is the first study to evaluate real-time respiratory dynamics and cardiac function during exposure and up to 24 h post-exposure to CRF. The evaluation of toxicological signs and respiratory dynamics following exposure to CRF will be useful in the development of therapeutic strategies to counteract the ongoing threat of abuse and overuse of opioids and their synthetic variants.

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Rebuttal from Peter M. Lalley, Paul M. Pilowsky, Hubert V. Forster and Edward J. Zuperku

Cited by 3 publications

References 10 publications

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

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

Opioid-induced Respiratory Depression Is Only Partially Mediated by the preBötzinger Complex in Young and Adult Rabbits In Vivo

Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone

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