Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn
- University of Newcastle, Australia
- University of Glasgow, United Kingdom
- Hokkaido University School of Medicine, Japan
Abstract
Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Health and Medical Research Council (631000)
- Robert J Callister
- Brett A Graham
National Health and Medical Research Council (1043933)
- Robert J Callister
- David I Hughes
- Brett A Graham
Biotechnology and Biological Sciences Research Council (BB/J000620/1)
- David I Hughes
Biotechnology and Biological Sciences Research Council (BB/P007996/1)
- David I Hughes
National Health and Medical Research Council (1144638)
- Robert J Callister
- Christopher V Dayas
- David I Hughes
- Brett A Graham
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Allan Basbaum, University of California, San Francisco, United States
Ethics
Animal experimentation: All studies carried out in Glasgow were in accordance with the European Community directive 86/609/EEC and UK Animals (Scientific Procedures) Act 1986. All studies carried out at University of Newcastle were in accordance with the Animal Research Act 1985 (NSW), under the guidelines of the National Health and Medical Research Council Code for the Care and Use of Animals for Scientific Purposes in Australia (2013). All animal handling and experimental procedures were performed under approved institutional animal care and ethics committee protocols (University of Newcastle: A-2013-312 and A2016-603; University of Glasgow)
Version history
- Received: June 10, 2019
- Accepted: November 9, 2019
- Accepted Manuscript published: November 12, 2019 (version 1)
- Version of Record published: December 12, 2019 (version 2)
Copyright
© 2019, Smith 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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Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn
eLife 8:e49190.
https://doi.org/10.7554/eLife.49190
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