Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine
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 cha...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/3/426 |
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| author | Yusuke Mizobuchi Kanako Miyano Sei Manabe Eiko Uezono Akane Komatsu Yui Kuroda Miki Nonaka Yoshikazu Matsuoka Tetsufumi Sato Yasuhito Uezono Hiroshi Morimatsu |
| author_facet | Yusuke Mizobuchi Kanako Miyano Sei Manabe Eiko Uezono Akane Komatsu Yui Kuroda Miki Nonaka Yoshikazu Matsuoka Tetsufumi Sato Yasuhito Uezono Hiroshi Morimatsu |
| author_sort | Yusuke Mizobuchi |
| collection | DOAJ |
| description | 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<sup>®</sup> 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. |
| first_indexed | 2024-03-09T20:05:12Z |
| format | Article |
| id | doaj.art-d1b1c66c5db7400385d1f700d98cb702 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T20:05:12Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-d1b1c66c5db7400385d1f700d98cb7022023-11-24T00:35:46ZengMDPI AGBiomolecules2218-273X2022-03-0112342610.3390/biom12030426Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with MorphineYusuke Mizobuchi0Kanako Miyano1Sei Manabe2Eiko Uezono3Akane Komatsu4Yui Kuroda5Miki Nonaka6Yoshikazu Matsuoka7Tetsufumi Sato8Yasuhito Uezono9Hiroshi Morimatsu10Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, JapanDepartment of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, JapanDepartment of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, JapanDepartment of Anesthesiology and Critical Care Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, JapanDepartment of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama-shi 700-8558, JapanThe 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<sup>®</sup> 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.https://www.mdpi.com/2218-273X/12/3/426µ-opioid receptordesensitizationtolerancefentanylmorphineketamine |
| spellingShingle | Yusuke Mizobuchi Kanako Miyano Sei Manabe Eiko Uezono Akane Komatsu Yui Kuroda Miki Nonaka Yoshikazu Matsuoka Tetsufumi Sato Yasuhito Uezono Hiroshi Morimatsu Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine Biomolecules µ-opioid receptor desensitization tolerance fentanyl morphine ketamine |
| title | Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine |
| title_full | Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine |
| title_fullStr | Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine |
| title_full_unstemmed | Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine |
| title_short | Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine |
| title_sort | ketamine improves desensitization of µ opioid receptors induced by repeated treatment with fentanyl but not with morphine |
| topic | µ-opioid receptor desensitization tolerance fentanyl morphine ketamine |
| url | https://www.mdpi.com/2218-273X/12/3/426 |
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