Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine
| العنوان: | Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine |
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| المؤلفون: | Aubrie A Harland, Steven G. Kinsey, Kim Wix, Shane W Kaski, Allison N White, Kristen R Trexler, Vincent Setola, Jeffrey Aubé, Terry P. Kenakin, David P. Siderovski, Joshua D Gross, Thomas E. Prisinzano |
| المصدر: | J Pharmacol Exp Ther |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Agonist, Special Section on The Opioid Crisis, Uremic pruritus, medicine.drug_class, Drug Evaluation, Preclinical, Receptors, Opioid, mu, Pharmacology, κ-opioid receptor, Mice, Random Allocation, 03 medical and health sciences, Drug Delivery Systems, 0302 clinical medicine, medicine, Animals, Spiro Compounds, Pain Measurement, Dose-Response Relationship, Drug, Morphine, business.industry, Receptors, Opioid, kappa, Drug Synergism, medicine.disease, Conditioned place preference, Mice, Inbred C57BL, 030104 developmental biology, Morphinans, Opioid, Molecular Medicine, Female, Analgesia, μ-opioid receptor, business, Locomotion, 030217 neurology & neurosurgery, Nalfurafine, medicine.drug |
| الوصف: | Mu opioid receptor (MOR)-targeting analgesics are efficacious pain treatments, but notorious for their abuse potential. In preclinical animal models, coadministration of traditional kappa opioid receptor (KOR)-targeting agonists with MOR-targeting analgesics can decrease reward and potentiate analgesia. However, traditional KOR-targeting agonists are well known for inducing antitherapeutic side effects (psychotomimesis, depression, anxiety, dysphoria). Recent data suggest that some functionally selective, or biased, KOR-targeting agonists might retain the therapeutic effects of KOR activation without inducing undesirable side effects. Nalfurafine, used safely in Japan since 2009 for uremic pruritus, is one such functionally selective KOR-targeting agonist. Here, we quantify the bias of nalfurafine and several other KOR agonists relative to an unbiased reference standard (U50,488) and show that nalfurafine and EOM-salvinorin-B demonstrate marked G protein-signaling bias. While nalfurafine (0.015 mg/kg) and EOM-salvinorin-B (1 mg/kg) produced spinal antinociception equivalent to 5 mg/kg U50,488, only nalfurafine significantly enhanced the supraspinal analgesic effect of 5 mg/kg morphine. In addition, 0.015 mg/kg nalfurafine did not produce significant conditioned place aversion, yet retained the ability to reduce morphine-induced conditioned place preference in C57BL/6J mice. Nalfurafine and EOM-salvinorin-B each produced robust inhibition of both spontaneous and morphine-stimulated locomotor behavior, suggesting a persistence of sedative effects when coadministered with morphine. Taken together, these findings suggest that nalfurafine produces analgesic augmentation, while also reducing opioid-induced reward with less risk of dysphoria. Thus, adjuvant administration of G protein-biased KOR agonists like nalfurafine may be beneficial in enhancing the therapeutic potential of MOR-targeting analgesics, such as morphine. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::590e1e6e2c01d88146faf230eeecacf0 https://doi.org/10.1124/jpet.118.255661 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....590e1e6e2c01d88146faf230eeecacf0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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