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

Abstract

Background and PurposeChronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to cataloguing diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses.Experimental approachTo 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 ResultsWe 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 signalling nodes. We investigated 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 spleen associated 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 and another Syk inhibitor P505‐15, significantly reversed pain hypersensitivity in both sexes.Conclusions and ImplicationsThus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.

Sex Differences in Visceral Pain and Comorbidities: Clinical Outcomes, Preclinical Models, and Cellular and Molecular Mechanisms

“…As for other pain modalities, an earlier study demonstrates that there are no striking differences in gene expression between male and female mice, while immune cell infiltration into DRG is sexually different in nerve injury pain [119]. A number of other studies [120][121][122][123][124][125] have also provided considerable amounts of datasets from RNAseq to reveal sex-differential changes in molecular signatures in DRG, the spinal cord, sciatic nerves, and brain tissues from mice and rats in pain, which are summarized in Table 2, to provide guidance for an in-depth investigation of pain-sexual dimorphism in the visceral organs and other tissues. RNAseq analysis of DRGs from more than 50 patients for the first time reveals profound sex-differential molecular signatures in pain and provides more objective measurements at the molecular levels.…”

Sex Differences in Visceral Pain and Comorbidities: Clinical Outcomes, Preclinical Models, and Cellular and Molecular Mechanisms

“…However, 146 genes (including Ahr, Fos, and Socs3) are elevated in female mice in CCI [97]. A number of other studies [98][99][100][101][102][103][104] have provided considerable sizes of datasets from RNAseq to reveal sex-differential changes in molecular signatures in DRG, spinal cord, sciatic nerves, and brain tissues from mice and rats in pain, which is summarized in Table 2, to provide a guidance for in-depth study of their physiological roles in pain sexual Table 2. Transcriptome analysis of tissues involved in pain processing to shed lights on sex differences at molecular levels.…”

Translational control in the spinal cord regulates gene expression and pain hypersensitivity in the chronic phase of neuropathic pain

“…The persistence of these changes relies on de novo gene expression, which is tightly regulated, primarily via transcriptional and translational control mechanisms. Whereas previous studies have characterized transcriptional [7][8][9][10][11] and translational 12,13 changes in the dorsal root ganglia (DRG) and spinal cord following peripheral nerve injury and have demonstrated their important roles during the early stage of neuropathic pain 12,14 , the investigations of these mechanisms in the late maintenance phase are lacking.…”