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Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats

  1. Stefan Hirschberg
  2. Yong Li
  3. Andrew Randall
  4. Eric J Kremer
  5. Anthony E Pickering  Is a corresponding author
  1. University of Bristol, United Kingdom
  2. University of Exeter, United Kingdom
  3. CNRS, France
Research Article
  • Cited 31
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Cite this article as: eLife 2017;6:e29808 doi: 10.7554/eLife.29808

Abstract

The locus coeruleus (LC) projects throughout the brain and spinal cord and is the major source of central noradrenaline. It remains unclear whether the LC acts functionally as a single global effector or as discrete modules. Specifically, while spinal-projections from LC neurons can exert analgesic actions, it is not known whether they can act independently of ascending LC projections. Using viral vectors taken up at axon terminals, we expressed chemogenetic actuators selectively in LC neurons with spinal (LC:SC) or prefrontal cortex (LC:PFC) projections. Activation of the LC:SC module produced robust, lateralised anti-nociception while activation of LC:PFC produced aversion. In a neuropathic pain model, LC:SC activation reduced hind-limb sensitization and induced conditioned place preference. By contrast, activation of LC:PFC exacerbated spontaneous pain, produced aversion and increased anxiety-like behaviour. This independent, contrasting modulation of pain-related behaviours mediated by distinct noradrenergic neuronal populations provides evidence for a modular functional organisation of the LC.

Article and author information

Author details

  1. Stefan Hirschberg

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Yong Li

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrew Randall

    Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Eric J Kremer

    IGMM, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Anthony E Pickering

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    For correspondence
    tony.pickering@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0345-0456

Funding

Wellcome (gr088373)

  • Anthony E Pickering

University of Bristol

  • Stefan Hirschberg
  • Andrew Randall
  • Anthony E Pickering

European Molecular Biology Organization

  • Stefan Hirschberg
  • Eric J Kremer
  • Anthony E Pickering

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures conformed to the UK Animals (Scientific Procedures) Act 1986, were performed under Home Office project licence (3003362) and were approved by the University of Bristol Animal Welfare and Ethical Review Board.

Reviewing Editor

  1. Allan Basbaum, University of California, San Francisco, United States

Publication history

  1. Received: June 21, 2017
  2. Accepted: October 11, 2017
  3. Accepted Manuscript published: October 13, 2017 (version 1)
  4. Version of Record published: October 23, 2017 (version 2)

Copyright

© 2017, Hirschberg et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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