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
  • 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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleNEUROPHARMACOLOGY

Deletion of the Glutamate Receptor 5 Subunit of Kainate Receptors Affects the Development of Morphine Tolerance

Johanna J. Bogulavsky, Ann M. Gregus, Paul T.-H. Kim, Alberto C. S. Costa, Anjali M. Rajadhyaksha and Charles E. Inturrisi
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 579-587; DOI: https://doi.org/10.1124/jpet.108.144121
Johanna J. Bogulavsky
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ann M. Gregus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul T.-H. Kim
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alberto C. S. Costa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anjali M. Rajadhyaksha
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles E. Inturrisi
  • 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

Previous reports utilizing pharmacological antagonists implicate kainate receptor (KAR) activation in the development of morphine tolerance, dependence, conditioned place preference (CPP), and locomotor sensitization, but the role of glutamate receptor (GluR) 5-containing KAR in these effects remains unclear because of limited selectivity of the inhibitors employed. Therefore, we examined responses to systemic morphine treatment in mice expressing a constitutive deletion of GluR5 [GluR5 knockout (KO)]. Unlike wild-type (WT) littermates, GluR5 KO mice do not develop tolerance after repeated morphine administration by subcutaneous injection or via subcutaneous pellet implantation. In contrast, GluR5 KO mice do not differ from WT with respect to thermal or mechanical nociceptive thresholds, acute morphine antinociception, morphine disposition in the central nervous system (CNS), morphine physical dependence as revealed by naloxone-precipitated withdrawal or development of place preference and locomotor hyperresponsiveness after chronic morphine administration. It is surprising that continuous subcutaneous infusion of the GluR2/GluR5-preferring antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] decreased the number of naloxone-precipitated jumps to a similar extent in WT and GluR5 KO mice. We observed opioid-induced hypersensitivity in both groups during morphine withdrawal as demonstrated by equivalent reductions in thermal and mechanical thresholds; however, this hypersensitivity was not evident during continuous systemic morphine infusion. These data collectively indicate that KARs containing the GluR5 subunit contribute to the development of morphine tolerance without affecting nociceptive thresholds, morphine analgesia, or disposition in CNS of morphine and its metabolite morphine-3-glucuronide. In addition, constitutive deletion of GluR5 does not alter the morphine-induced increase in locomotor activity or the acquisition of morphine reward as measured by a CPP paradigm.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA001457, DA000198, Training Grant DA007274, and Center Grant DA005130].

  • J.J.B. and A.M.G. contributed equally to this work.

  • High-performance liquid chromatography and mass spectrometry of morphine and M3G in WT and GluR5 KO mice were conducted by Drs. Rodger Foltz and David Andrenyak at the Center for Human Toxicology of the University of Utah (Salt Lake City, UT) under a services contract to NIDA and Dr. H. Singh of the Division of Neuroscience and Behavioral Research at NIDA. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.144121.

  • ABBREVIATIONS: CNS, central nervous system; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GluR, glutamate receptor; KAR, kainate receptor; AMPAR, AMPA receptor; LY293558, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid; CPP, conditioned place preference; KO, knockout; WT, wild type; TTW, thermal tail withdrawal; CI, confidence interval; PWL, paw withdrawal latency; M3G, morphine-3-glucuronide; ANOVA, analysis of variance; LY382884, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid; PKC, protein kinase C; SC, spinal cord.

    • Received July 28, 2008.
    • Accepted October 27, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
  • 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 Journal of Pharmacology and Experimental Therapeutics 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.
Deletion of the Glutamate Receptor 5 Subunit of Kainate Receptors Affects the Development of Morphine Tolerance
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleNEUROPHARMACOLOGY

Deletion of the Glutamate Receptor 5 Subunit of Kainate Receptors Affects the Development of Morphine Tolerance

Johanna J. Bogulavsky, Ann M. Gregus, Paul T.-H. Kim, Alberto C. S. Costa, Anjali M. Rajadhyaksha and Charles E. Inturrisi
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 579-587; DOI: https://doi.org/10.1124/jpet.108.144121

Citation Manager Formats

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

Deletion of the Glutamate Receptor 5 Subunit of Kainate Receptors Affects the Development of Morphine Tolerance

Johanna J. Bogulavsky, Ann M. Gregus, Paul T.-H. Kim, Alberto C. S. Costa, Anjali M. Rajadhyaksha and Charles E. Inturrisi
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 579-587; DOI: https://doi.org/10.1124/jpet.108.144121
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • P-Glycoprotein Apical Efflux Ratio for Compound Optimization
  • Pharmacology of Carbamate Insecticides at Melatonin Receptors
  • Metalloporphyrins modify disease outcomes in parkinsonism
Show more Neuropharmacology

Similar Articles

  • 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 JPET
  • 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
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics