Analysis of potential pathogenic factors of trigeminal neuralgia in rats

doi:10.19439/j.sjos.2023.01.007

Abstract

Abstract: PURPOSES: Transcriptomics-based analysis of key transcriptional molecules in the pathogenesis of trigeminal neuropathic pain was conducted to screen key molecules in the pathogenesis of trigeminal neuralgia. METHODS: Rat trigeminal nerve pathological pain model, namely chronic constriction injury of distal infraorbital nerve (IoN-CCI), was constructed and animal behaviors postsurgery were observed and analyzed. Trigeminal ganglia were collected for RNA-seq transcriptomics analysis. StringTie was used to annotate and quantify genome expression. DESeq2 was applied to compare between groups with P value less than 0.05 and fold change greater than 2 times and less than 0.5 times to screen differential genes, and display them with volcano graphs and cluster graphs. ClusterProfiler software was used to perform GO function enrichment analysis of differential genes. RESULTS: On the fifth postoperative day (POD5), the rat's face-grooming behavior increased to a peak; on the seventh postoperative day (POD7), the von-frey value dropped to the lowest value, indicating that the mechanical pain threshold of rats was significantly decreased. RNA-seq analysis of IoN-CCI rat ganglia found that the significantly up-regulated signaling pathways included B cell receptor signaling pathway, cell adhesion, complement and coagulation cascade pathways; significantly down-regulated pathways were related to systemic lupus erythematosus. Multiple genes among Cacna1s, Cox8b, My1, Ckm, Mylpf, Myoz1, Tnnc2 were involved in mediating the occurrence of trigeminal neuralgia. CONCLUSIONS: B cell receptor signaling pathway, cell adhesion, complement and coagulation cascade pathways, neuroimmune pathways are closely related to the occurrence of trigeminal neuralgia. The interaction of multiple genes among Cacna1s, Cox8b, My11, Ckm, Mylpf, Myoz1, Tnnc2 leads to the occurrence of trigeminal neuralgia.

Key words: Trigeminal neuralgia, RNA-Seq, Neuropathic pain

CLC Number:

R782.4

LIU Yue-min, CHAI Ying, WEI Wen-bin, LIU Zhi-yang, HAN Zi-xiang, CHEN Min-jie. Analysis of potential pathogenic factors of trigeminal neuralgia in rats[J]. Shanghai Journal of Stomatology, 2023, 32(1): 33-39.

References

[1] De Toledo IP, Conti Réus J, Fernandes M, et al.Prevalence of trigeminal neuralgia: a systematic review[J]. J Am Dent Assoc, 2016, 147(7): 570-576.
[2] Di Stefano G, Maarbjerg S, Nurmikko T, et al.Triggering trigeminal neuralgia[J]. Cephalalgia, 2018, 38(6): 1049-1056.
[3] Gambeta E, Chichorro JG, Zamponi GW, et al.Trigeminal neuralgia: an overview from pathophysiology to pharmacological treatments[J]. Mol Pain, 2020, 16: 1744806920901890.
[4] 顿英俏, 纪俊宇, 张亚楠, 等. 三叉神经痛的研究进展[J]. 沈阳药科大学学报, 2020, 37(10): 949-955.
[5] Höftberger R, Lassmann H.Inflammatory demyelinating diseases of the central nervous system[J]. Handb Clin Neurol, 2017, 145(3): 263-283.
[6] Liu MX, Zhong J, Xia L, et al.A correlative analysis between inflammatory cytokines and trigeminal neuralgia or hemifacial spasm[J]. Neurol Res, 2019, 41(4): 335-340.
[7] Andres KH, von Düring M, Muszynski K. Nerve fibres and their terminals of the dura mater encephali of the rat[J]. Anat Embryol (Berl), 1987,175(3): 289-301.
[8] Messlinger K, Hanesch U, Baumgärtel M.Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity[J]. Anat Embryol (Berl), 1993, 188(3): 219-237.
[9] Wang C, Liu H, Yang M, et al.RNA-Seq based transcriptome analysis of endothelial differentiation of bone marrow mesenchymal stem cells[J]. Eur J Vasc Endovasc Surg, 2020, 59(5): 834-842.
[10] Ayturk U.RNA-seq in skeletal biology[J]. Curr Osteoporos Rep, 2019, 17(4): 178-185.
[11] Ding W, You Z, Shen S, et al.An improved rodent model of trigeminal neuropathic pain by unilateral chronic constriction injury of distal infraorbital nerve[J]. J Pain, 2017, 18(8): 899-907.
[12] Bennett GJ, Xie YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man[J]. Pain,1988, 33(1): 87-107.
[13] Araújo-Filho HG, Pereira EWM, Campos AR, et al.Chronic orofacial pain animal models-progress and challenges[J]. Expert Opin Drug Discov, 2018, 13(10): 949-964.
[14] Deseure K, Hans GH.Chronic constriction injury of the rat's infraorbital nerve (IoN-CCI) to study trigeminal neuropathic pain[J]. J Vis Exp, 2015(103): 53167.
[15] Love MI, Huber W, Anders S.Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2[J]. Genome Biol, 2014, 15(12): 550-570.
[16] Jaggi AS, Jain V, Singh N.Animal models of neuropathic pain[J]. Fundam Clin Pharmacol, 2011, 25(1):1-28.
[17] Challa SR.Surgical animal models of neuropathic pain: pros and cons[J]. Int J Neurosci, 2015, 125(3): 170-174.
[18] Sacerdote P, Franchi S, Trovato AE, et al.Transient early expression of TNF-a sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy[J]. Neurosci Lett, 2008, 436(2): 210-213.
[19] Martucci C, Trovato AE, Costa B, et al.The purinergic antagonist PPADS reduces pain related behaviours and interleukin-1 beta, interleukin-6, iNOS and nNOS overproduction in central and peripheral nervous system after peripheral neuropathy in mice[J]. Pain, 2008, 137(1): 81-95.
[20] De Vry J, Kuhl E, Franken-Kunkel P, et al.Pharmacological characterization of the chronic constriction injury model of neuropathic pain[J]. Eur J Pharmacol, 2004, 491(2-3): 137-148.
[21] Beam TA, Loudermilk EF, Kisor DF.Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia[J]. Physiol Genomics, 2017, 49(2): 81-87.
[22] Sangkuhl K, Dirksen RT, Alvarellos ML, et al.PharmGKB summary: very important pharmacogene information for CACNA1S[J]. Pharmacogenet Genomics, 2020, 30(2): 34-44.
[23] Schartner V, Romero NB, Donkervoort S, et al.Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy[J]. Acta Neuropathol, 2017, 133(4): 517-533.
[24] Mei Y, Barrett JE, Hu H.Calcium release-activated calcium channels and pain[J]. Cell Calcium, 2018, 74: 180-185.
[25] Dou Y, Xia J, Gao R, et al.Orai1 plays a crucial role in central sensitization by modulating neuronal excitability[J]. J Neurosci, 2018, 38(4): 887-900.
[26] Gao X, Han S, Huang Q, et al.Calcium imaging in population of dorsal root ganglion neurons unravels novel mechanisms of visceral pain sensitization and referred somatic hypersensitivity[J]. Pain, 2021, 162(4): 1068-1081.
[27] Price RD, Yamaji T, Yamamoto H, et al.FK1706, a novel non-immunosuppressive immunophilin: neurotrophic activity and mechanism of action[J]. Eur J Pharmacol, 2005, 509(1): 9-11.
[28] Yamazaki S, Yamaji T, Murai N, et al.FK1706, a novel non-immunosuppressive immunophilin ligand, modifies gene expression in the dorsal root ganglia during painful diabetic neuropathy[J]. Neurol Res, 2012, 34(5):469-477.
[29] Fatoba O, Itokazu T, Yamashita T.Complement cascade functions during brain development and neurodegeneration[J]. FEBS J, 2022, 289(8):2085-2109.
[30] Warwick CA, Keyes AL, Woodruff TM, et al.The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain[J]. J Biol Chem, 2021, 297(3): 101085.
[31] Shutov LP, Warwick CA, Shi X, et al.The complement system component C5a produces thermal hyperalgesia via macrophage-to-nociceptor signaling that requires NGF and TRPV1[J]. J Neurosci, 2016, 36(18): 5055-5070.
[32] Wu S, Lutz BM, Miao X, et al.Dorsal root ganglion transcriptome analysis fol- lowing peripheral nerve injury in mice[J]. Mol Pain, 2016, 12: 1744806916629048.
[33] Stevens AM, Liu L, Bertovich D, et al.Differential expression of neuroinflammatory mRNAs in the rat sciatic nerve following chronic constriction injury and pain-relieving nanoemulsion NSAID delivery to infiltrating macrophages[J]. Int J Mol Sci, 2019, 20(21): 5269-5292.
[34] Uttam S, Wong C, Amorim IS, et al.Translational profiling of dorsal root ganglia and spinal cord in a mouse model of neuropathic pain[J]. Neurobiol Pain, 2018, 4(1): 35-44.
[35] Stevens AM, Saleem M, Deal B, et al.Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats[J]. Mol Pain, 2020,16: 1744806920943309.