Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home
  • Log in
  • My Cart

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
Research Article

Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

Bora Inceoglu, Ahmed Bettaieb, Carlos A. Trindade da Silva, Kin Sing Stephen Lee, Fawaz G. Haj, and Bruce D. Hammock
  1. aDepartment of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
  2. bNutrition Department, University of California, Davis, CA 95616;
  3. cDepartment of Internal Medicine, University of California, Davis, CA 95616

See allHide authors and affiliations

PNAS first published July 6, 2015; https://doi.org/10.1073/pnas.1510137112
Bora Inceoglu
aDepartment of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ahmed Bettaieb
bNutrition Department, University of California, Davis, CA 95616;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carlos A. Trindade da Silva
aDepartment of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kin Sing Stephen Lee
aDepartment of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fawaz G. Haj
bNutrition Department, University of California, Davis, CA 95616;
cDepartment of Internal Medicine, University of California, Davis, CA 95616
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: bdhammock@ucdavis.edu fghaj@ucdavis.edu
Bruce D. Hammock
aDepartment of Entomology and UC Davis Cancer Center, University of California, Davis, CA 95616;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: bdhammock@ucdavis.edu fghaj@ucdavis.edu
  1. Contributed by Bruce D. Hammock, June 1, 2015 (sent for review January 9, 2015; reviewed by Andrea G Hohmann and Daniele Piomelli)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

Significance

Here we define the causative role of endoplasmic reticulum (ER) stress on selective modulation of pain signaling. High levels of ER stress and neuropathic pain in diabetic animals are reduced using ER stress blockers. In healthy animals, turning on the ER stress signal transduction cascade generates an immediate but lasting and site restricted painful phenotype, which is reversible by ER stress blockers. This previously unnoticed mechanism explains the broad lack of efficacy of available analgesics and should ignite the discovery of a new generation of therapeutics that do not directly quell ion channel or neurotransmitter activity.

Abstract

Despite intensive effort and resulting gains in understanding the mechanisms underlying neuropathic pain, limited success in therapeutic approaches have been attained. A recently identified, nonchannel, nonneurotransmitter therapeutic target for pain is the enzyme soluble epoxide hydrolase (sEH). The sEH degrades natural analgesic lipid mediators, epoxy fatty acids (EpFAs), therefore its inhibition stabilizes these bioactive mediators. Here we demonstrate the effects of EpFAs on diabetes induced neuropathic pain and define a previously unknown mechanism of pain, regulated by endoplasmic reticulum (ER) stress. The activation of ER stress is first quantified in the peripheral nervous system of type I diabetic rats. We demonstrate that both pain and markers of ER stress are reversed by a chemical chaperone. Next, we identify the EpFAs as upstream modulators of ER stress pathways. Chemical inducers of ER stress invariably lead to pain behavior that is reversed by a chemical chaperone and an inhibitor of sEH. The rapid occurrence of pain behavior with inducers, equally rapid reversal by blockers and natural incidence of ER stress in diabetic peripheral nervous system (PNS) argue for a major role of the ER stress pathways in regulating the excitability of the nociceptive system. Understanding the role of ER stress in generation and maintenance of pain opens routes to exploit this system for therapeutic purposes.

  • endoplasmic reticulum stress
  • pain
  • diabetes
  • tunicamycin
  • soluble epoxide hydrolase

Footnotes

  • ↵1B.I. and A.B. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: bdhammock{at}ucdavis.edu or fghaj{at}ucdavis.edu.
  • Author contributions: B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. designed research; B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. performed research; A.B., K.S.S.L., F.G.H., and B.D.H. contributed new reagents/analytic tools; B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. analyzed data; and B.I., A.B., C.A.T.d.S., K.S.S.L., F.G.H., and B.D.H. wrote the paper.

  • Reviewers: A.G.H., Indiana University; and D.P., University of California, Irvine.

  • Conflict of interest statement: B.I., K.S.S.L., and B.D.H. are co-inventors on patents related to sEH by the University of California. B.D.H. and B.I. are co-founders of EicOsis LLC.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1510137112/-/DCSupplemental.

Next
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
ER stress drives pain
Bora Inceoglu, Ahmed Bettaieb, Carlos A. Trindade da Silva, Kin Sing Stephen Lee, Fawaz G. Haj, Bruce D. Hammock
Proceedings of the National Academy of Sciences Jul 2015, 201510137; DOI: 10.1073/pnas.1510137112

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
ER stress drives pain
Bora Inceoglu, Ahmed Bettaieb, Carlos A. Trindade da Silva, Kin Sing Stephen Lee, Fawaz G. Haj, Bruce D. Hammock
Proceedings of the National Academy of Sciences Jul 2015, 201510137; DOI: 10.1073/pnas.1510137112
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 118 (16)
Current Issue

Submit

Sign up for Article Alerts

Jump to section

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Water from a faucet fills a glass.
News Feature: How “forever chemicals” might impair the immune system
Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
Image credit: Shutterstock/Dmitry Naumov.
Reflection of clouds in the still waters of Mono Lake in California.
Inner Workings: Making headway with the mysteries of life’s origins
Recent experiments and simulations are starting to answer some fundamental questions about how life came to be.
Image credit: Shutterstock/Radoslaw Lecyk.
Cave in coastal Kenya with tree growing in the middle.
Journal Club: Small, sharp blades mark shift from Middle to Later Stone Age in coastal Kenya
Archaeologists have long tried to define the transition between the two time periods.
Image credit: Ceri Shipton.
Mouse fibroblast cells. Electron bifurcation reactions keep mammalian cells alive.
Exploring electron bifurcation
Jonathon Yuly, David Beratan, and Peng Zhang investigate how electron bifurcation reactions work.
Listen
Past PodcastsSubscribe
Panda bear hanging in a tree
How horse manure helps giant pandas tolerate cold
A study finds that giant pandas roll in horse manure to increase their cold tolerance.
Image credit: Fuwen Wei.

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Subscribers
  • Librarians
  • Press
  • Cozzarelli Prize
  • Site Map
  • PNAS Updates
  • FAQs
  • Accessibility Statement
  • Rights & Permissions
  • About
  • Contact

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490