Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 487-499 |
| Number of pages | 13 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 371 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2019 |
Bibliographical note
Funding Information:This work was supported, in part, by the E.J. Van Liere Medicine Professor Endowment (to D.P.S.) and by research grants from the National Institutes of Health National Institute on Drug Abuse to T.E.P. [R01 DA018151], to D.P.S. [R01 DA048153], and to S.G.K. [R03 DA039335]. J.D.G. and S.W.K. each acknowledge prior support from an National Institute of General Medical Sciences Behavioral & Biomedical Sciences training grant [T32 GM081741] and current support from National Institute on Drug Abuse predoctoral NRSA fellowships [F31 DA043331 and F30 DA044711, respectively]. We thank Dr. Gilad Barnea (Brown University) for furnishing HTLA cells for Tango assays and Dr. Liz Engler-Chiurazzi for access to, and advice with, the WVU Rodent Behavioral Core facility.
Funding Information:
This work was supported, in part, by the E.J. Van Liere Medicine Professor Endowment (to D.P.S.) and by research grants from the National Institutes of Health National Institute on Drug Abuse to T.E.P. [R01 DA018151], to D.P.S. [R01 DA048153], and to S.G.K. [R03 DA039335]. J.D.G. and S.W.K. each acknowledge prior support from an National Institute of General Medical Sciences Behavioral & Biomedical Sciences training grant [T32 GM081741] and current support from National Institute on Drug Abuse predoctoral NRSA fellowships [F31 DA043331 and F30 DA044711, respectively]. https://doi.org/10.1124/jpet.118.255661. s This article has supplemental material available at jpet.aspetjournals.org.
Publisher Copyright:
© 2019 American Society for Pharmacology and Experimental Therapy. All rights reserved.
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology