PT - JOURNAL ARTICLE AU - Kate L. White AU - J. Elliott Robinson AU - Hu Zhu AU - Jeffrey F. DiBerto AU - Prabhakar R. Polepally AU - Jordan K. Zjawiony AU - David E. Nichols AU - C. J. Malanga AU - Bryan L. Roth TI - The G Protein–Biased <em>κ</em>-Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo AID - 10.1124/jpet.114.216820 DP - 2015 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 98--109 VI - 352 IP - 1 4099 - http://jpet.aspetjournals.org/content/352/1/98.short 4100 - http://jpet.aspetjournals.org/content/352/1/98.full SO - J Pharmacol Exp Ther2015 Jan 01; 352 AB - 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.