Rebuttal from Gaspard Montandon and Richard Horner

Abstract

We agree with Lalley et al. (2014) that various brainstem sites may contribute to opioid-induced respiratory depression. Our focus here, however, is on respiratory rate depression by systemically administered drugs acting on μ-opioid receptors. Of all the potential neural sites where systemically administered μ-opioids could act, Lalley et al. suggest that the parabrachial/Kolliker–Fuse complex may be critically mediating respiratory rate depression. First, if pontine nuclei were responsible for rate suppression, then depression should not be observed in the absence of the pons. Still, respiratory slowing occurs in preparations where transections are performed caudal to the pons (Takita et al. 1997; Gray et al. 1999). Also, the blocking of μ-opioid receptors alone in pontine regions has a stimulatory effect on respiratory rate that can be misinterpreted as a reversal of opioid-induced respiratory depression (Phillips et al. 2012; Prkic et al. 2012). Using microdialysis tools to locally manipulate cells, we showed that the preBotC is highly sensitive to μ-opioid receptor agonists and mediates respiratory rate depression by systematically administered μ-opioids (Montandon et al. 2011). One caveat raised when using local drug application is that drug concentration in tissue is unknown as diffusion depends on the molecule, concentration and route of perfusion. To circumvent these issues, we designed strategies to assess how effective drug perfusion is. First, we simulated drug diffusion ex situ and found that after 2 h of perfusion less than 18% of the delivered concentration was present beside the probe membrane and 5% was found at a 1 mm distance (Grace et al. 2014), which invalidates the notion that drugs diffuse beyond the preBotC and affect other respiratory nuclei. Secondly, perfusion close to the preBotC was more potent in causing rate depression or its reversal than perfusion further away (Montandon et al. 2011). Also, if the μ-opioid receptor antagonist naloxone was affecting other nuclei, it should also block the impact of systemic μ-opioids on genioglossus muscle activity since the hypoglossal premotor/motor neurons are close to the preBotC. It did not, however, and we previously revealed separate medullary sites for hypoglossal motor suppression (Hajiha et al. 2009; Montandon et al. 2011). In conclusion, we dispute the belief that the preBotC plays an indirect role in opioid-induced respiratory rate depression. Other sites may indeed mediate other components of respiratory depression, such as reduced respiratory drive transmission and upper airway dysfunction, but based on the evidence discussed (Montandon et al. 2011), we restate that the preBotC plays a critical role in mediating opioid-induced respiratory rate depression.