Abstract
The hypothesis that functionally selective G protein–coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein–biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein–biased agonists have not been available to test this idea. Here we provide data using a G protein–biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein–biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein–biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein–biased KOR agonists.
Footnotes
- Received May 19, 2014.
- Accepted October 10, 2014.
This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA017204 and P01-DA035764]; and the National Institutes of Health National Institute of Mental Health Psychoactive Drug Screening Program.
A preliminary account of this work was previously presented at the following meeting: White KL, Vardy E, and Roth BL (2013) Utilizing functionally selective ligands to probe specific signaling pathways of the kappa opioid receptor. 2013 Kappa Therapeutics Meeting; 2013 Apr 24–27; Cambridge, MA.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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