Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
Molecular Pharmacology
  • 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
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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 molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Allosteric Interactions between δ and κ Opioid Receptors in Peripheral Sensory Neurons

Kelly A. Berg, Matthew P. Rowan, Achla Gupta, Teresa A. Sanchez, Michelle Silva, Ivone Gomes, Blaine A. McGuire, Philip S. Portoghese, Kenneth M. Hargreaves, Lakshmi A. Devi and William P. Clarke
Molecular Pharmacology February 2012, 81 (2) 264-272; DOI: https://doi.org/10.1124/mol.111.072702
Kelly A. Berg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew P. Rowan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Achla Gupta
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Teresa A. Sanchez
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle Silva
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ivone Gomes
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Blaine A. McGuire
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip S. Portoghese
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenneth M. Hargreaves
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lakshmi A. Devi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William P. Clarke
  • 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 + SI
  • PDF
Loading

Abstract

The peripheral δ opioid receptor (DOR) is an attractive target for analgesic drug development. There is evidence that DOR can form heteromers with the κ-opioid receptor (KOR). As drug targets, heteromeric receptors offer an additional level of selectivity and, because of allosteric interactions between protomers, functionality. Here we report that selective KOR antagonists differentially altered the potency and/or efficacy of DOR agonists in primary cultures of adult rat peripheral sensory neurons and in a rat behavioral model of thermal allodynia. In vitro, the KOR antagonist nor-binaltorphimine (nor-BNI) enhanced the potency of [d-Pen2,5]-enkephalin (DPDPE), decreased the potency of [d-Ala2,d-Leu5]-enkephalin (DADLE), and decreased the potency and efficacy of 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC80) to inhibit prostaglandin E2 (PGE2)-stimulated adenylyl cyclase activity. In vivo, nor-BNI enhanced the effect of DPDPE and decreased the effect of SNC80 to inhibit PGE2-stimulated thermal allodynia. In contrast to nor-BNI, the KOR antagonist 5′-guanidinonaltrindole (5′-GNTI) reduced the response of DPDPE both in cultured neurons and in vivo. Evidence for DOR-KOR heteromers in peripheral sensory neurons included coimmunoprecipitation of DOR with KOR, a DOR-KOR heteromer selective antibody augmented the antinociceptive effect of DPDPE in vivo, and the DOR-KOR heteromer agonist 6′-GNTI inhibited adenylyl cyclase activity in vitro as well as PGE2-stimulated thermal allodynia in vivo. Taken together, these data suggest that DOR-KOR heteromers exist in rat primary sensory neurons and that KOR antagonists can act as modulators of DOR agonist responses most likely through allosteric interactions between the protomers of the DOR-KOR heteromer.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA024865] (to W.P.C.), [Grant DA026619] (to K.A.B.), [Grant DA008863] (to L.A.D.); and [Grant DA01533] (to P.S.P.); and the National Institutes of Health National Institute of Dental and Craniofacial Research [Grant DE14318] (to M.P.R., B.A.M.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.072702.

  • ABBREVIATIONS:

    BK
    bradykinin
    DPDPE
    [d-Pen2,5]-enkephalin
    PGE2
    prostaglandin E2
    TG
    trigeminal ganglion
    DADLE
    [d-Ala2,d-Leu5]-enkephalin
    MOR
    μ opioid receptor
    KOR
    κ opioid receptor
    DOR
    δ-opioid receptor
    6′-GNTI
    6′-guanidinonaltrindole
    nor-BNI
    nor-binaltorphimine
    CB
    cannabinoid
    HEK
    human embryonic kidney
    PVDF
    polyvinyl difluoride
    BK
    bradykinin
    PWL
    paw withdrawal latency
    NTI
    naltrindole
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    AT1
    angiotensin II type 1.

  • Received April 4, 2011.
  • Accepted November 9, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm 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

Molecular Pharmacology: 81 (2)
Molecular Pharmacology
Vol. 81, Issue 2
1 Feb 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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 Molecular Pharmacology 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.
Allosteric Interactions between δ and κ Opioid Receptors in Peripheral Sensory Neurons
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Allosteric Interactions between DOR and KOR

Kelly A. Berg, Matthew P. Rowan, Achla Gupta, Teresa A. Sanchez, Michelle Silva, Ivone Gomes, Blaine A. McGuire, Philip S. Portoghese, Kenneth M. Hargreaves, Lakshmi A. Devi and William P. Clarke
Molecular Pharmacology February 1, 2012, 81 (2) 264-272; DOI: https://doi.org/10.1124/mol.111.072702

Citation Manager Formats

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

Share
Research ArticleArticle

Allosteric Interactions between DOR and KOR

Kelly A. Berg, Matthew P. Rowan, Achla Gupta, Teresa A. Sanchez, Michelle Silva, Ivone Gomes, Blaine A. McGuire, Philip S. Portoghese, Kenneth M. Hargreaves, Lakshmi A. Devi and William P. Clarke
Molecular Pharmacology February 1, 2012, 81 (2) 264-272; DOI: https://doi.org/10.1124/mol.111.072702
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Cysteine151 in Keap1 Drives CDDO-Me Pharmacodynamic Action
  • Allosteric Modulation of Metabotropic Glutamate Receptor 1
  • Mechanism of Selective Action of Paraherquamide A
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • 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
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

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