Desensitization and Tolerance of Mu Opioid Receptors on Pontine Kölliker-Fuse Neurons

Abstract

Acute desensitization of mu opioid receptors is thought to be an initial step in the development of tolerance to opioids. Given the resistance of the respiratory system to develop tolerance, desensitization of neurons in the Kölliker-Fuse (KF), a key area in the respiratory circuit, was examined. The activation of G protein-coupled inwardly rectifying potassium current was measured using whole-cell voltage-clamp recordings from KF and locus coeruleus (LC) neurons contained in acute rat brain slices. A saturating concentration of the opioid agonist [Met]-enkephalin (ME) caused significantly less desensitization in KF neurons compared with LC neurons. In contrast to LC, desensitization in KF neurons was not enhanced by activation of protein kinase C or in slices from morphine-treated rats. Cellular tolerance to ME and morphine was also lacking in KF neurons from morphine-treated rats. The lack of cellular tolerance in KF neurons correlates with the relative lack of tolerance to the respiratory depressant effect of opioids.

Maternal Methadone Destabilizes Neonatal Breathing and Desensitizes Neonates to Opioid-Induced Respiratory Frequency Depression

“…However, we used repetitive daily methadone injections in the same rats from P0 to P5 and, in many other physiological systems, opioids induce tolerance within the first few exposures in rodents (Ling et al, 1989). Tolerance in the respiratory system has been observed after daily acute fentanyl (Laferrière et al, 2005), though this has not been observed in other studies (Emery et al, 2016;Levitt and Williams, 2018). Here, we found no evidence for tolerance after repeated daily acute methadone exposure, but we demonstrate the unique finding that opioid sensitivity is blunted acutely after MM.…”

“…Here, we found no evidence for tolerance after repeated daily acute methadone exposure, but we demonstrate the unique finding that opioid sensitivity is blunted acutely after MM. Furthermore, it is widely thought the respiratory control system does not develop opioid-induced tolerance ( Emery et al, 2016 ; Levitt and Williams, 2018 ), which increases vulnerability of patients to lethal respiratory frequency depression with opioid over-use. Thus, the demonstration of blunted opioid sensitivity represents a unique finding regarding sensitivity of developing neurorespiratory networks to opioids.…”

Neurochemistry of the Kölliker‐Fuse nucleus from a respiratory perspective

“…While the exact variant of GABA‐B receptors in the KF is currently not known, acute KF slice experiments conducted in our laboratory provide functional evidence for the presence of GABA‐B receptors on KF neurons. Application of the GABA‐B agonist baclofen leads to the activation of G‐protein‐coupled inwardly rectifying K + (GIRK) conductance in a large population (~60%) of KF neurons in both rats and mice (Levitt, Abdala, Paton, Bissonnette, & Williams, 2015; Levitt & Williams, 2018; Varga, Reid, Kieffer, & Levitt, 2020). Furthermore, GABA‐B receptor positive neurons are also sensitive to opioids (Levitt & Williams, 2018; Varga et al., 2020).…”

“…Application of the GABA-B agonist baclofen leads to the activation of G-protein-coupled inwardly rectifying K + (GIRK) conductance in a large population (~60%) of KF neurons in both rats and mice (Levitt, Abdala, Paton, Bissonnette, & Williams, 2015;Levitt & Williams, 2018;Varga, Reid, Kieffer, & Levitt, 2020). Furthermore, GABA-B receptor positive neurons are also sensitive to opioids (Levitt & Williams, 2018;Varga et al, 2020).…”

Recent Progress in Opioid Research from an Electrophysiological Perspective

“…In locus coeruleus, the decline in the peak outward current is about 50% during the application of a saturating concentration of an efficacious agonist. There are examples of neurons in which the decline in current is nearly complete (cholinergic striatal interneurons, personal observation) and other examples such as neurons in the Kolliker-Fuse in which there is little or no acute decline ( Levitt and Williams, 2018 ). Further, in the locus coeruleus, mechanisms of desensitization may change over time, as it has been observed that desensitization in older rats was homologous (occurring at MOR), whereas desensitization in younger rats appeared heterologous (affecting signaling through multiple receptors) ( Llorente et al, 2012 ).…”