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

Abstract

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. 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. 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. 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.

Regulation of neuropathic pain by microglial Orai1 channels

“…Is the upregulation in IBA1 labelling induced by SNI due to altered Orai1 expression? Despite the evidence for involvement of Orai1 in mitigating pain hypersensitivity and reducing microglial reactivity in male mice, RNA-seq analysis of the lumbar spinal cord ( 80 ) indicated that SNI did not evoke changes in the expression of Orai1 nor in the expression of other SOCE molecules including Orai2, STIM1, and STIM2 (Figure S10) . Similarly, no change in expression of the SOCE transcriptome was detected in female mice (Figure S10) .…”

Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem

“…The top hit from this analysis was fostamatinib, which targets the nonreceptor tyrosine kinase Syk. Administrating the active metabolite of fostamatinib, R406, intrathecally significantly reversed SNI-induced pain hypersensitivity in both sexes (112).…”

“…Studies of PNI-induced transcriptomic changes are often focused on sex differences, but many of the DEGs are similar between the sexes. A cross-species, cross-sex study investigating spinal cord transcriptomes after SNI from mice and rats of both sexes revealed an overall positive correlation between the sexes in both species (112). The PNI-induced transcriptional reprogramming imputed commonalities, as well as differences, in cellular pathways and gene regulation.…”

Regulation of neuropathic pain by microglial Orai1 channels

“…RNA-seq analysis of spinal tissue from male and female mice is described in a companion study (52). Briefly, the L4-L5 lumbar dorsal horn of the spinal cord was harvested on postoperative day 7 to study transcriptional changes in dorsal spinal tissue.…”

“…Genes with adjusted P values <0.01 and fold changes greater than 0.5 were defined as differentially expressed genes. A total of 24 samples from mice were analyzed [divided between the Sham-ipsi, Sham-contra, and SNI_ipsi groups; see (52)].…”