Potential Molecular Pathway Linking Caffeine Exposure to Trigeminal Neuralgia
An In Silico Study
DOI:
https://doi.org/10.5195/d3000.2026.1605Klíčová slova:
caffeine, trigeminal neuralgia, pathways, bioinformaticAbstrakt
Trigeminal neuralgia is a debilitating neuropathic pain disorder characterized by recurrent, brief, electric shock-like facial pain. Although caffeine is widely consumed and has neuroinflammatory modulation ability, its potential molecular association with trigeminal neuralgia remains unclear. This study aimed to investigate potential molecular pathways linking caffeine exposure to trigeminal neuralgia-related biological processes. Compound-disease datasets were obtained from CTD database. Gene-gene interaction network was constructed with GeneMANIA. GO and KEGG pathway enrichment analysis were performed using DAVID bioinformatics (p-value set to 0.05; FDR-correction applied). Cell-type specific gene-expression were assessed using single-cell data from HPA server. Eight overlapping genes —FOS, GFAP, GRIN1, IL1B, MAPK1, MAPK3, MAPK9, and TNF— were recognized in caffeine-trigeminal neuralgia datasets. Gene-gene interaction network showed predominence predicted and physical interaction. Biological processes, cellular components, molecular functions, and pathway enrichment analysis were obtained. HPA analysis demonstrated gene expression across vascular and immune cell populations. Molecular overlaps, biological frameworks and pathways, showed potential trigeminal sensitization through neuroinflammation, glial response, MAPK signaling, immune-cell interaction and neural excitability. These findings provide computational evidence of potential molecular links between caffeine and mechanism underlying trigeminal neuralgia.
Reference
1. Shankar Kikkeri N, Nagalli S. Trigeminal Neuralgia. StatPearls Publishing, Treasure Island (FL). Preprint posted online 2026.
2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
3. Ashina S, Robertson CE, Srikiatkhachorn A, et al. Trigeminal neuralgia. Nat Rev Dis Primers. 2024;10(1):39.
4. Mousavi SH, Lindsey JW, Westlund KN, Alles SRA. Trigeminal Neuralgia as a Primary Demyelinating Disease: Potential Multimodal Evidence and Remaining Controversies. J Pain. 2024;25(2):302-311.
5. Cho S, Kim KM, Chu MK. Coffee consumption and migraine: a population-based study. Sci Rep. 2024;14(1):6007.
6. Benson SM, Unice KM, Glynn ME. Hourly and daily intake patterns among U.S. caffeinated beverage consumers based on the National Health and Nutrition Examination Survey (NHANES, 2013–2016). Food and Chemical Toxicology. 2019;125:271-278.
7. Holle D, Heber A, Naegel S, Diener HC, Katsarava Z, Obermann M. Influences of smoking and caffeine consumption on trigeminal pain processing. J Headache Pain. 2014;15(1):39.
8. Salmaso V, Menin S, Moro S, Spalluto G, Federico S. Adenosine Receptors in Neuroinflammation and Neurodegeneration. Cells. 2025;14(20):1585.
9. Rodrigues DR, Mariano DCB, Santos LHS, Tagliati CA. ToxAnalyzer: A user-friendly web tool for interactive data analysis and visualization of chemical compounds from the Comparative Toxicogenomics Database (CTD)TM. Computational Toxicology. 2021;19:100170.
10. Franz M, Rodriguez H, Lopes C, et al. GeneMANIA update 2018. Nucleic Acids Res. 2018;46(W1):W60-W64.
11. Sofi MY, Shafi A, Masoodi KZ. Database for annotation, visualisation and integrated discovery. Bioinformatics for Everyone. Published online January 1, 2022:177-185.
12. Tang D, Chen M, Huang X, et al. SRplot: A free online platform for data visualization and graphing. PLoS One. 2023;18(11):e0294236.
13. Wendel M, Carabelly AN, Utami JP. An In Silico Study on Target Gene Identification and Oral Health Conditions Linked to Coal Dust Exposure. Pollution. 2025;11(4):1057-1069.
14. Karlsson M, Zhang C, Méar L, et al. A single–cell type transcriptomics map of human tissues. Sci Adv. 2021;7(31).
15. Xu Y, Fan Y, Li R, et al. Trigeminal neuralgia: from clinical challenges to molecular insights. J Headache Pain. 2026;27(1):197.
16. Shen K, Liu X, Gao Z, Liu D, Fu J. A single-cell immune cell atlas of trigeminal neuralgia identifies cross-lineage programs linked to carbamazepine resistance. J Headache Pain. Published online September 3, 2026.
17. Lin J, Qianming C. Kir4.1 Regulates The Orofacial Pain After Trigeminal Nerve Injury. Int Dent J. 2025;75:104074.
18. Liu S, Crawford J, Maltezos H, Sun Y, Tao R, Tao F. A glutamatergic brain neural circuit is critical for modulating trigeminal neuropathic pain. Pain. 2025;166(11):2529-2540.
19. Kamada J, Hamanaka T, Oshimo A, et al. Glial Fibrillary Acidic Protein’s Usefulness as an Astrocyte Biomarker Using the Fully Automated LUMIPULSE® System. Diagnostics (Basel). 2024;14(22).
20. Lin J, Fang X, Ou M, et al. Glial inwardly rectifying potassium channel 4.1 regulates secretion of BDNF and GDNF via ERK1/2 MAP kinases in trigeminal neuropathic pain. Int J Biol Macromol. 2025;317:144811.
21. Arini DS, Perdana LP, Fabillar J, et al. Systemic curcumin administration mitigates neuropathic pain in a rat model of trigeminal neuralgia by suppressing TNF-α and pSTAT3 signaling. Mol Pain. 2026;22.
22. Qiu CJ, Cui ZY, Zhang Q, Pan SJ, Pei BG. Perioperative changes in inflammatory biomarkers and underlying molecular mechanisms in patients with trigeminal neuralgia undergoing surgical interventions. Front Neurol. 2025;16.
23. Bai F, Song Y, Cao Y, et al. Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway. Int J Mol Sci. 2022;23(13):7065.
24. Zhai X, Lin X, Zhang L, et al. Phosphoproteomics uncovers a neuroimmune perspective on trigeminal neuralgia: sexually dimorphic regulatory networks linking calcium channels to the complement cascade. Front Immunol. 2026;17.
25. Zhang Y, Song N, Liu F, et al. Activation of mitogen-activated protein kinases in satellite glial cells of the trigeminal ganglion contributes to substance P-mediated inflammatory pain. Int J Oral Sci. 2019;11(3):24.
26. He ZL, Xu C, Yang QF, et al. NPY-Y2R driven neuroimmune signaling as a potential therapeutic target for trigeminal neuralgia: clinical and experimental evidence. Sci Bull (Beijing). 2026;71(13):3363-3379.
27. Li X, Liu Y, Shao M, et al. Exploring the mechanism of Nav1.3 in the ION-CCI rat model based on the TLR4/TRAF6/NF-κB pathway. Neurosci Lett. 2024;832:137806.
28. Wang Z, Wang H, Wang Z, et al. Liquiritin attenuates IONI-induced trigeminal neuropathic pain via TLR4/MyD88-dependent modulation of microglial M1-like polarization. Int Immunopharmacol. 2026;177:116554.
29. Gao SJ, Liu L, Li DY, et al. Interleukin-17: A Putative Novel Pharmacological Target for Pathological Pain. Curr Neuropharmacol. 2024;22(2):204-216.
30. Chen H, Tang X, Li J, et al. IL-17 crosses the blood–brain barrier to trigger neuroinflammation: a novel mechanism in nitroglycerin-induced chronic migraine. J Headache Pain. 2022;23(1):1.
31. Shen Y, Li M, Jin S, et al. The role of interleukins in peripheral nerve injury and the current status of treatment. Front Immunol. 2026;16.
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