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.

Reviewing Editor

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

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).

Version 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.

Metrics

  • 3,505
    views
  • 432
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.65156

Further reading

    1. Genetics and Genomics
    2. Neuroscience
    Bohan Zhu, Richard I Ainsworth ... Javier González-Maeso
    Research Article

    Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.

    1. Neuroscience
    Aedan Yue Li, Natalia Ladyka-Wojcik ... Morgan Barense
    Research Article

    Combining information from multiple senses is essential to object recognition, core to the ability to learn concepts, make new inferences, and generalize across distinct entities. Yet how the mind combines sensory input into coherent crossmodal representations - the crossmodal binding problem - remains poorly understood. Here, we applied multi-echo fMRI across a four-day paradigm, in which participants learned 3-dimensional crossmodal representations created from well-characterized unimodal visual shape and sound features. Our novel paradigm decoupled the learned crossmodal object representations from their baseline unimodal shapes and sounds, thus allowing us to track the emergence of crossmodal object representations as they were learned by healthy adults. Critically, we found that two anterior temporal lobe structures - temporal pole and perirhinal cortex - differentiated learned from non-learned crossmodal objects, even when controlling for the unimodal features that composed those objects. These results provide evidence for integrated crossmodal object representations in the anterior temporal lobes that were different from the representations for the unimodal features. Furthermore, we found that perirhinal cortex representations were by default biased towards visual shape, but this initial visual bias was attenuated by crossmodal learning. Thus, crossmodal learning transformed perirhinal representations such that they were no longer predominantly grounded in the visual modality, which may be a mechanism by which object concepts gain their abstraction.