Evidence map›Paper›PMID 25320048›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2015

The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.

Kate L White, J Elliott Robinson, Hu Zhu, Jeffrey F DiBerto, Prabhakar R Polepally, Jordan K Zjawiony, David E Nichols, C J Malanga, Bryan L Roth

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 135 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
135citing papers in PubMed, 1 pooled it
6.8field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

135 citing papers in PubMed, 1 synthesis or guideline pooled it, 200 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Triazole 187 is a biased KOR agonist that suppresses itch without sedation and induces anxiolytic-like behaviors in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026
    Article
  4. Article
  5. Review
  6. Review
  7. Agonism and Biased Signaling.Handbook of experimental pharmacology · 2026
    Review
  8. Article
  9. Review
  10. Review
  11. Bidirectional Modification of aACS central science · 2025
    Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Review
  19. Article
  20. Review

75 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

Kate L WhiteDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
J Elliott RobinsonDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
Hu ZhuDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
Jeffrey F DiBertoDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
Prabhakar R PolepallyDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
Jordan K ZjawionyDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
David E NicholsDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
C J MalangaDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.).
Bryan L RothDepartment of Pharmacology (K.L.W., H.Z., D.E.N., B.L.R.), Department of Neurology (J.E.R., J.F.D., C.J.M.), and Bowles Center for Alcohol Studies (J.E.R., C.J.M.), University of North Carolina, Chapel Hill, North Carolina; and Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.) bryan_roth@med.unc.edu.
University of Mississippi · USUniversity of North Carolina at Chapel Hill · US

Funding

Structure-Function of Opioid ReceptorsP01DA035764 · NIDA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI CHEREZOV, VADIM, ROTH, BRYAN L. · 2014 to 2018
$7.1M
PREDOCTORAL TRAINING IN PHARMACOLOGICAL SCIST32GM007040 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI NICHOLAS, ROBERT A · 1985 to 2019
$6.0M
Diterpines as Selective Kappa Opioid Receptor AgonistsR01DA017204 · NIDA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROTH, BRYAN L. · 2003 to 2014
$3.2M
Mechanisms of Alcohol Reward in a Humanized OPRM1 Mouse ModelF30AA021312 · NIAAA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROBINSON, JOHN ELLIOTT · 2012 to 2016
$149k
NIAAA NIH HHS F30 AA021312NIDA NIH HHS P01 DA035764NIDA NIH HHS P01-DA035764NIDA NIH HHS R01 DA017204NIDA NIH HHS R01-DA017204NIGMS NIH HHS T32 GM007040
6 · The paper itself

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.

Indexed as

Analgesics, OpioidAnimalsArrestinsbeta-Arrestin 2beta-ArrestinsConditioning, PsychologicalDiterpenes, ClerodaneGTP-Binding ProteinsHEK293 CellsHumansLigandsMiceReceptors, Opioid, kappaSignal Transduction22-thiocyanatosalvinorin AAnalgesics, OpioidARRB2 protein, humanArrb2 protein, mouseArrestinsbeta-Arrestin 2beta-ArrestinsDiterpenes, ClerodaneGTP-Binding ProteinsLigandsReceptors, Opioid, kappa

Identifiers

PMID25320048
PMCPMC4279099
OpenAlexW2076323933

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.