Further investigation of the rapid-onset and short-duration action of the G protein-biased μ-ligand oliceridine
| Autor: | Yoshiyuki Iwase, Takamichi Arima, Kanako Miyano, Michiko Narita, Minoru Narita, Yukari Suda, Naoko Kuzumaki, Shigeru Sasaki, Tomohisa Mori, Yusuke Hamada, Kazuyuki Sugita, Kimio Higashiyama, Shoki Matsumura, Yasuhito Uezono, Mitsuaki Yamazaki, Akinobu Matsuzawa, Takayasu Yamauchi, Yoshinori Takemura |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Time Factors G protein Oliceridine Gi alpha subunit Receptors Opioid mu Biophysics Thiophenes Pharmacology Biochemistry Cell Line Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine GTP-Binding Proteins medicine Animals Humans Spiro Compounds Receptor Molecular Biology Sensitization Analgesics Mice Inbred ICR Cell Biology Ligand (biochemistry) 030104 developmental biology medicine.anatomical_structure Nociception chemistry 030220 oncology & carcinogenesis Neuralgia Animal studies Signal Transduction |
| Zdroj: | Biochemical and Biophysical Research Communications. 534:988-994 |
| ISSN: | 0006-291X |
| Popis: | TRV130 (oliceridine), a G protein-biased ligand for μ-opioid receptor, has recently been synthesized. It is considered to have strong antinociceptive effects and only minor adverse effects. However, whether or not oliceridine actually exhibits an ideal pharmacological profile as an analgesic has not yet been fully clarified in animal studies. This study examined the pharmacological profile of oliceridine in cells and animals. Oliceridine (10 μM) did not produce any μ-opioid receptor internalization in cells even though it increased impedance, which reflects the activation of Gi protein using the CellKey™ system, and inhibited the formation of cAMP. In mice, oliceridine (0.3–10 mg/kg) produced a dose-dependent antinociceptive effect with a rapid-onset and short-duration action in the hot-plate test, as well as antihyperalgesia after sciatic nerve ligation without the development of antinociceptive tolerance using the thermal hyperalgesia test. On the other hand, oliceridine inhibited gastrointestinal transit. Furthermore, oliceridine produced rapid-onset hyperlocomotion at antinociceptive doses; sensitization developed in mice and an emetic effect was observed in ferrets. These results indicate that, although oliceridine may produce dopamine-related behaviors even through selective stimulation of the G-protein-biased μ-opioid receptor pathway, it still offers advantages for breakthrough pain without antinociceptive tolerance with adequate doses. |
| Databáze: | OpenAIRE |
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