Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity
- University of California, San Francisco, United States
- University of California San Francisco, United States
- Flinders University, Australia
Abstract
Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally-directed, dendrites and ventrally-directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data file is available for figure 6.
Article and author information
Author details
Ida J Llewellyn-Smith
Funding
Sir Henry Wellcome Fellowship (092208/Z/10/Z)
- Line S Löken
Ake Wiberg Foundation
- Line S Löken
NIH Blueprint for Neuroscience Research (R35NS097306)
- Allan Basbaum
Wellcome Trust (A102645)
- Allan Basbaum
Open Philanthropy Project
- Allan Basbaum
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Rohini Kuner, Universität Heidelberg, Germany
Ethics
Animal experimentation: Mice were housed in cages on a standard 12:12 hour light/dark cycle with food and water ad libitum. Permission for all animal experiments was obtained and overseen by the Institutional Animal Care and Use Committee (IACUC) at the University of California San Francisco. All experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the recommendations of the International Association for the Study of Pain. Ethical approval number: AN183265; expires Feb. 26, 2023.
Version history
- Received: June 7, 2020
- Accepted: May 29, 2021
- Accepted Manuscript published: June 1, 2021 (version 1)
- Version of Record published: June 30, 2021 (version 2)
Copyright
© 2021, Löken 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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Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity
eLife 10:e59751.
https://doi.org/10.7554/eLife.59751
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