Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine

Abstract

The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of μ-opioid receptors (MORs). We measured changes in MOR activity and intracellular signaling induced by repeated fentanyl and morphine administration and investigated the effects of ketamine on these changes with human embryonic kidney 293 cells expressing MOR using the CellKey™, cADDis cyclic adenosine monophosphate, and PathHunter® β-arrestin recruitment assays. Repeated administration of fentanyl or morphine suppressed the second MOR responses. Administration of ketamine before a second application of opioids within clinical concentrations improved acute desensitization and enhanced β-arrestin recruitment elicited by fentanyl but not by morphine. The effects of ketamine on fentanyl were suppressed by co-treatment with an inhibitor of G-protein-coupled receptor kinase (GRK). Ketamine may potentially reduce fentanyl tolerance but not that of morphine through modulation of GRK-mediated pathways, possibly changing the conformational changes of β-arrestin to MOR.

Recent advances in the study of anesthesia-and analgesia-related mechanisms of S-ketamine

“…Opioid receptor activation reduces intracellular cAMP production and decreases Ca 2+ channel and TRPV-1 channel activity in the spinal dorsal root ganglion (DRG), which attenuates pain signaling and produces an analgesic effect ( Stein, 2016 ; Reeves et al, 2022 ). Long-term opioid use can lead to intracellular “cAMP rescue”, which reduces cAMP concentrations to normal levels, thereby reducing the analgesic effects of opioids and causing drug tolerance ( Kibaly et al, 2017 ; Mizobuchi et al, 2022 ). According to the study, ketamine activates G-protein-coupled receptor kinase 2/3, activating the μ receptor phosphorylation site, thereby reducing the intracellular cAMP concentration and inhibiting the onset of “cAMP rescue”, which may be one of the reasons why ketamine can ameliorate tolerance to long-term opioid use ( Kibaly et al, 2017 ; Mizobuchi et al, 2022 ).…”

“…Long-term opioid use can lead to intracellular “cAMP rescue”, which reduces cAMP concentrations to normal levels, thereby reducing the analgesic effects of opioids and causing drug tolerance ( Kibaly et al, 2017 ; Mizobuchi et al, 2022 ). According to the study, ketamine activates G-protein-coupled receptor kinase 2/3, activating the μ receptor phosphorylation site, thereby reducing the intracellular cAMP concentration and inhibiting the onset of “cAMP rescue”, which may be one of the reasons why ketamine can ameliorate tolerance to long-term opioid use ( Kibaly et al, 2017 ; Mizobuchi et al, 2022 ). Notably, ketamine also enhances β-arrestin recruitment during this process and increases the amount of β-blocker binding to the tail conformation of the μ-receptor (which induces resensitization), which improved desensitization ( Cahill et al, 2017 ; Mizobuchi et al, 2022 ).…”

“…According to the study, ketamine activates G-protein-coupled receptor kinase 2/3, activating the μ receptor phosphorylation site, thereby reducing the intracellular cAMP concentration and inhibiting the onset of “cAMP rescue”, which may be one of the reasons why ketamine can ameliorate tolerance to long-term opioid use ( Kibaly et al, 2017 ; Mizobuchi et al, 2022 ). Notably, ketamine also enhances β-arrestin recruitment during this process and increases the amount of β-blocker binding to the tail conformation of the μ-receptor (which induces resensitization), which improved desensitization ( Cahill et al, 2017 ; Mizobuchi et al, 2022 ). In addition, opioid receptor activation also inhibits excitatory postsynaptic currents evoked by glutamate receptors in the spinal cord ( Stein, 2016 ), so antagonism of the ionotropic glutamate receptor NMDA by S-ketamine may indirectly produce a synergistic effect of opioid receptor activation and exert analgesic effects.…”