Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

  1. Robert A R Drake  Is a corresponding author
  2. Kenneth A Steel
  3. Richard Apps
  4. Bridget M Lumb
  5. Anthony E Pickering
  1. University of Bristol, United Kingdom
  2. University of Cardiff, United Kingdom

Abstract

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemo-genetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

Data availability

All data generated or analysed are included in the manuscript

Article and author information

Author details

  1. Robert A R Drake

    Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    For correspondence
    robert.drake@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2381-7198
  2. Kenneth A Steel

    School of Biosciences, University of Cardiff, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Richard Apps

    School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Bridget M Lumb

    School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0268-6419
  5. Anthony E Pickering

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    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

Medical Research Council (MR/P00668/X1)

  • Robert A R Drake
  • Richard Apps
  • Bridget M Lumb
  • 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 experimental and surgical procedures were conducted in accordance with the UK Animals (Scientific Procedures) Act (1998) and local Animal Welfare and Ethical Review Body (AWERB).

Reviewing Editor

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

Publication history

  1. Received: November 24, 2020
  2. Accepted: February 7, 2021
  3. Accepted Manuscript published: February 8, 2021 (version 1)
  4. Version of Record published: February 19, 2021 (version 2)

Copyright

© 2021, Drake 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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  1. Robert A R Drake
  2. Kenneth A Steel
  3. Richard Apps
  4. Bridget M Lumb
  5. Anthony E Pickering
(2021)
Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats
eLife 10:e65156.
https://doi.org/10.7554/eLife.65156

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