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Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain
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  • Shahrzad Ghazisaeidi,
  • Milind Muley,
  • YuShan Tu,
  • Mahshad Kolahdouzan,
  • Ameet Sengar,
  • Arun Ramani,
  • Michael Brudno,
  • Michael Salter
Shahrzad Ghazisaeidi
University of Toronto

Corresponding Author:[email protected]

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Milind Muley
Hospital for Sick Children Research Institute
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YuShan Tu
Hospital for Sick Children Research Institute
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Mahshad Kolahdouzan
University of Toronto
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Ameet Sengar
Hospital for Sick Children Research Institute
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Arun Ramani
Hospital For Sick Children
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Michael Brudno
University of Toronto
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Michael Salter
University of Toronto
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Background and Purpose: Chronic pain is a devastating problem affecting 1 in 5 individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics and data mining have contributed to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Experimental approach: Here, with the goal of identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species and imputed commonalities, as well as differences in cellular pathways and gene regulation. Key Results: We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signaling nodes. We interrogated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase Syk, which our analysis had identified as a key node in the interactome. Conclusions & Implications : We found that intrathecally administrating the active metabolite of fostamatinib, R406, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.
22 Aug 2022Submitted to British Journal of Pharmacology
15 Sep 2022Submission Checks Completed
15 Sep 2022Assigned to Editor
23 Sep 2022Reviewer(s) Assigned
20 Oct 2022Review(s) Completed, Editorial Evaluation Pending
27 Oct 2022Editorial Decision: Revise Minor
28 Apr 20231st Revision Received
03 May 2023Review(s) Completed, Editorial Evaluation Pending
03 May 2023Submission Checks Completed
03 May 2023Assigned to Editor
21 May 2023Reviewer(s) Assigned
03 Jun 2023Editorial Decision: Accept