Transcriptome-wide analysis of trigeminal ganglion and subnucleus caudalis in a mouse model of chronic constriction injury-induced trigeminal neuralgia

Abstract

Trigeminal neuropathic pain (TNP) induces mechanical allodynia and hyperalgesia, which are known to alter gene expression in injured dorsal root ganglia primary sensory neurons. Non-coding RNAs (ncRNAs) have been linked to TNP. However, the functional mechanism underlying TNP and the expression profile of ncRNAs in the trigeminal ganglion (TG) and trigeminal subnucleus caudalis (Sp5C) are still unknown. We used RNA sequencing and bioinformatics analysis to examine the TG and Sp5C transcriptomes after infraorbital nerve chronic constrictive injury (IoN-CCI). The robust changes in the gene expression of lncRNAs, circRNAs, and mRNAs were observed within the TG and Sp5C from mice that underwent IoN-CCI and the sham-operated mice (day 7). In total, 111,003 lncRNAs were found in TG and 107,157 in Sp5C; 369 lncRNAs were differentially expressed in TG, and 279 lncRNAs were differentially expressed in Sp5C. In addition, 13,216 circRNAs in TG and 21,658 circRNAs in Sp5C were identified, with 1,155 circRNAs and 2,097 circRNAs differentially expressed in TG and Sp5C, respectively. Furthermore, 5,205 DE mRNAs in TG and 3,934 DE mRNAs in Sp5C were differentially expressed between IoN-CCI and sham groups. The study revealed a high correlation of pain-related differentially expressed genes in the TG and Sp5C to anxiety, depression, inflammation, neuroinflammation, and apoptosis. Gene Ontology analysis revealed that binding-related molecular functions and membrane-related cell components were significantly enriched. Kyoto Encyclopedia of Genes and Genomes analysis shows the most significant enrichments in neurogenesis, nervous system development, neuron differentiation, adrenergic signaling, cAMP signaling, MAPK signaling, and PI3K-Akt signaling pathways. Furthermore, protein–protein interaction analysis showed that hub genes were implicated in neuropeptide signaling pathways. Functional analysis of DE ncRNA-targeting genes was mostly enriched with nociception-related signaling pathways underpinning TNP. Our findings suggest that ncRNAs are involved in TNP development and open new avenues for research and treatment.

Post-Traumatic Trigeminal Neuropathy: Neurobiology and Pathophysiology

“…The majority of evidence comes from animal models of neuropathic pain that study injury to the spinal nerve. The cascade of events from peripheral to central in the nervous system result in major changes to neurons and their environment and may be affected by genetic variations [ 5 , 6 ].…”

“…Recent studies have found missense mutations in both genes that encode the pore forming α1 subunit of the voltage-gated calcium channels, Cav3.1 and 3.2, resulting in gain of function and contributing to chronic pain [ 20 , 21 ]. Animal models of neuropathic pain involving chronic constriction injury of the infraorbital nerve have demonstrated that non-coding RNAs are involved in the development of trigeminal pain [ 6 , 22 ]. Following nerve injury, micro RNAs are downregulated in the dorsal root ganglion, which is thought to increase pain [ 23 ].…”