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

Yusuke Mizobuchi,Kanako Miyano,Yui Kuroda,Yoshikazu Matsuoka,Eiko Uezono,Miki Nonaka,Sei Manabe,Akane Komatsu,Yasuhito Uezono,Tetsufumi Sato,Hiroshi Morimatsu

doi:10.3390/biom12030426

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.

Highlights

Opioids have been used for the relief of cancer [1], perioperative [2], and criticalillness-related [3] pain, but increase in usage due to tolerance is an issue that should be addressed [4–6]
We evaluated the changes in may involve improved desensitization of μ-opioid receptors (MORs) activity with repeated administration of the same doses of fentanyl and morphine with the CellKeyTM system, which can detect G-protein-coupled receptor (GPCR) activity as change in cellular impedance [26]
We investigated the effects of CMPD101 and U0126 on the ketamine-induced enhancement of β-arrestin recruitment to MOR induced by repeated fentanyl administration as was performed for the CellKeyTM and cADDis cAMP assays

Summary

Introduction

Opioids have been used for the relief of cancer [1], perioperative [2], and criticalillness-related [3] pain, but increase in usage due to tolerance is an issue that should be addressed [4–6]. Tolerance is defined as a reduction in drug efficacy due to prolonged or repeated administration, leading to reduced drug effects and increased dosage to maintain the analgesic effects. These dosage increases may accelerate the appearance of side effects, including respiratory depression, constipation, and addiction [7]. Biomolecules 2022, 12, 426 metabolism, and initiation of compensatory/opponent processes [8,9]. The major subtypes include μ-(MOR), δ-(DOR), κ-(KOR), and nociceptin (NOR), whereas opioid analgesics are mainly mediated by MOR [10,11]

Methods

Results

Discussion

Conclusion