Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Pharmacological Reviews
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Pharmacological Reviews

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit Pharm Rev on Facebook
  • Follow Pharm Rev on Twitter
  • Follow ASPET on LinkedIn
Review ArticleReview Article

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Kirsten M. Raehal, Cullen L. Schmid, Chad E. Groer and Laura M. Bohn
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews December 2011, 63 (4) 1001-1019; DOI: https://doi.org/10.1124/pr.111.004598
Kirsten M. Raehal
Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cullen L. Schmid
Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chad E. Groer
Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura M. Bohn
Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David R. Sibley
Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, Florida
Roles: ASSOCIATE EDITOR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through activation of the μ opioid receptor; however, an increasing number of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examined, or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.

Footnotes

  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.111.004598.

  • 1 Abbreviations:

    CaMKII
    calcium/calmodulin kinase II
    CaV
    voltage-gated calcium channel
    CHO
    Chinese hamster ovary
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    DRG
    dorsal root ganglion
    ERK1/2
    extracellular regulated kinase 1/2
    FRET
    fluorescence resonance energy transfer
    GF109203X
    3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride
    Gö6976
    12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole
    GPCR
    G protein-coupled receptor
    GRIN1
    glutamate receptor subunit ζ 1
    GRK
    G protein-coupled receptor kinase
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    HA
    hemagglutinin
    HEK
    human embryonic kidney
    JNK
    c-jun N-terminal kinase
    Kir3
    G protein-coupled inwardly rectifying potassium channel
    KO
    knockout
    μOR
    μ opioid receptor
    MOR
    μ opioid receptor
    MEF
    mouse embryonic fibroblast
    PKA
    protein kinase A
    PKC
    protein kinase C
    Ro32-0432
    3-[(8S)-8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl[-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione hydrochloride
    siRNA
    small interfering RNA
    WT
    wild type.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

PharmRev articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Pharmacological Reviews: 63 (4)
Pharmacological Reviews
Vol. 63, Issue 4
1 Dec 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Pharmacological Reviews article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance
(Your Name) has forwarded a page to you from Pharmacological Reviews
(Your Name) thought you would be interested in this article in Pharmacological Reviews.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Review ArticleReview Article

FUNCTIONAL SELECTIVITY AT THE μOR

Kirsten M. Raehal, Cullen L. Schmid, Chad E. Groer and Laura M. Bohn
Pharmacological Reviews December 1, 2011, 63 (4) 1001-1019; DOI: https://doi.org/10.1124/pr.111.004598

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Review ArticleReview Article

FUNCTIONAL SELECTIVITY AT THE μOR

Kirsten M. Raehal, Cullen L. Schmid, Chad E. Groer and Laura M. Bohn
Pharmacological Reviews December 1, 2011, 63 (4) 1001-1019; DOI: https://doi.org/10.1124/pr.111.004598
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • I. Introduction
    • II. Biased Agonism with Respect to G Protein Coupling
    • III. Biased Agonism with Respect to Activation of Second Messengers
    • IV. Biased Agonism with Respect to μOR Phosphorylation
    • V. Biased Agonism with Respect to Recruitment of β-Arrestin2
    • VI. Biased Agonism with Respect to Receptor Desensitization
    • VII. Biased Agonism with Respect to Receptor Internalization
    • VIII. Biased Agonism with Respect to β-Arrestin-Mediated Signaling
    • IX. Biased Agonism and Antinociceptive Tolerance
    • X. Conclusions
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier
  • Review of Natural Language Processing in Pharmacology
  • PHARMACOGENOMICS: Driving Personalized Medicine
Show more Review Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Pharmacological Reviews
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacology Research & Perspectives
ISSN 1521-0081 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics