Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine
Yusuke Mizobuchi,
Kanako Miyano,
Sei Manabe,
Eiko Uezono,
Akane Komatsu,
Yui Kuroda,
Miki Nonaka,
Yoshikazu Matsuoka,
Tetsufumi Sato,
Yasuhito Uezono,
Hiroshi Morimatsu
Affiliations
Yusuke Mizobuchi
Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, Japan
Kanako Miyano
Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
Sei Manabe
Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, Japan
Eiko Uezono
Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
Akane Komatsu
Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Yui Kuroda
Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Miki Nonaka
Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
Yoshikazu Matsuoka
Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, Japan
Tetsufumi Sato
Department of Anesthesiology and Critical Care Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Yasuhito Uezono
Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
Hiroshi Morimatsu
Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, Japan
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.
