Conserved transcriptional programming across sex and species after
peripheral nerve injury predicts treatments for neuropathic pain
Abstract
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.