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Transcriptional profiling of non-injured nociceptors after spinal cord injury reveals diverse molecular changes

Jessica R. Yasko, Isaac L. Moss, View ORCID ProfileRichard E. Mains
doi: https://doi.org/10.1101/743567
Jessica R. Yasko
University of Connecticut Health Center, Department of Neuroscience, Farmington CT 06030
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Isaac L. Moss
University of Connecticut Health Center, Department of Orthopedic Surgery and the Comprehensive Spine Center, Farmington CT 06030
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Richard E. Mains
University of Connecticut Health Center, Department of Neuroscience, Farmington CT 06030
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  • ORCID record for Richard E. Mains
  • For correspondence: mains@uchc.edu
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Abstract

Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons distal to the site of injury may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15g for 1 minute. Alterations in gene expression produce long-term sensory changes, therefore we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting. RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.

Contribution to the field Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain. Much of the pain seems to emanate from tissues further away from the brain than the site of injury. Chronic pain develops weeks to months after injury, which means that patients are frequently treated only after enduring pain has developed. Nociceptors are the specialized sensory neurons central to chronic pain. We were interested in studying SCI-induced gene transcript (RNA) changes before the onset of chronic pain, in the hope of identifying mechanisms which could become therapeutic targets. Nociceptors below the site of spinal injury were isolated and their RNAs were sequenced. The results identified a unique pattern of gene expression in the subpopulation of nociceptors projecting to the relevant peripheral tissue. Particularly interesting were sets of genes crucial to synapse formation and maturation – the ability of neurons to talk to each other – and genes involved in inflammatory responses, since treatment of inflammation of nervous tissue could also be important for therapeutic approaches. It is evident that the transition from acute to chronic pain occurs in distinct steps that involve numerous signaling pathways, providing a host of potential new drug targets.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 22, 2019.
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Transcriptional profiling of non-injured nociceptors after spinal cord injury reveals diverse molecular changes
Jessica R. Yasko, Isaac L. Moss, Richard E. Mains
bioRxiv 743567; doi: https://doi.org/10.1101/743567
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Transcriptional profiling of non-injured nociceptors after spinal cord injury reveals diverse molecular changes
Jessica R. Yasko, Isaac L. Moss, Richard E. Mains
bioRxiv 743567; doi: https://doi.org/10.1101/743567

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