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.

Behavioral characterization of G-protein-coupled receptor 160 knockout mice

“…4 Furthermore, Gpr160 is upregulated in the spinal cord in both male and female mice and rats that underwent spared nerve injury. 31 In addition to animal models of neuropathic pain, Gpr160 is also expressed in patients with neuropathic pain. Indeed, a recent study identified Gpr160 as one of the top pain-associated genes upregulated in the dorsal root ganglion in a cohort of female patients with neuropathic pain who underwent thoracic vertebrectomy surgery for spinal reconstruction or tumor resection.…”

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

“…This causes concerns surrounding the validity of many mechanisms and targets that were identified in older studies that predominantly used male rodents, and raises the question of whether therapeutics that were developed through studies done mostly in one species will translate to another species, much less humans (Mogil, 2016). In a new paper published in British Journal of Pharmacology , Ghazisaeidi and colleagues have taken a comprehensive approach to examining transcriptional changes in the spinal dorsal horn in response to peripheral nerve injury in both sexes in mice and rats (Ghazisaeidi et al, 2023). We think that their experimental design sets a new standard for the field for focusing on pain mechanisms and identifies targets that have the best probability for meaningful clinical translation.…”