Background & Aims

Neuropathic pain, an intractable pain in the orofacial region, is thought to be caused by increased excitability of trigeminal ganglion (TG) neurons. Accumulating evidence indicates the importance of proinflammatory cytokines in the development of orofacial neuropathic pain. We have identified interleukin (IL)-33 as a novel cytokine involved in neuropathic pain in the trigeminal spinal subnucleus caudalis. However, the roles of IL-33 in the TG in orofacial neuropathic pain have not yet been elucidated. This study aimed to analyze the role of IL-33 in the TG in the development of neuropathic pain using an infraorbital nerve injury model.

Methods

Male C57BL/6J mice underwent partial ligation of the infraorbital nerve using 5-0 silk thread (IONI: infraorbital nerve injury). In sham mice, the infraorbital nerve was exposed and then the wound was closed without ligation. In some experiments, a cannula was implanted in the TG of naïve mice. Then, drugs were administered through the implanted cannula. Siamese mice were exposed to the infraorbital nerve and then the wound was closed without ligation. Head-withdrawal threshold (HWT) was measured by stimulation of whisker pad skin with von Frey filaments. Immunohistochemical and western blot analyses were performed.

Results

A decrease in HWT to mechanical stimulation of the whisker pad skin was initiated from day 1 after IONI, whereas HWT was unchanged in sham mice throughout the experimental period. On day 5 after IONI, we observed a significant increase in IL-33 in the TG. Neutralization of IL-33 in the TG suppressed the development of mechanical allodynia in the whisker pad skin after IONI. Conversely, IL-33 administration in the TG caused mechanical allodynia in the whisker pad skin in naïve mice. Immunohistochemical analysis revealed that IL-33 was exclusively expressed in fibroblasts in the TG. Removal of fibroblast in the TG abolished IL-33 expression in the TG after IONI and delayed IONI-induced mechanical allodynia in the whisker pad skin. We also found that ST2, an IL-33 receptor, was expressed in TG neurons, especially TRPA1-positive TG neurons. Intra-TG administration of IL-33 facilitated membrane translocation of TRPA1. Mechanical allodynia caused by intra-TG administration of IL-33 was suppr

Conclusions

Our data suggest that fibroblast-derived IL-33 enhances membrane translocation of TRPA1, leading to the development of mechanical allodynia.

References

Kimura et al., IL-33 induces orofacial neuropathic pain through Fyn-dependent phosphorylation of GluN2B in the trigeminal spinal subnucleus caudalis, Brain, Behavior, and Immunity 99. 2022, 266–280.

Trevisan et al., TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain, 2016, 1361-1377.

Chen et al., Interleukin-33 Promotes Serotonin Release from Enterochromaffin Cells for Intestinal Homeostasis, immunity 54, 2021, 151-163.

Schmidt et al., Various signals involved in nociception regulate TRPA1 levels at the plasma membrane, Neuron, 2009, 498-509.

Presenting Author

Yosuke Ikehata

Poster Authors

Yosuke Ikehata

DDS

Showa uni

Lead Author

E-mail

yosuke ikehata DDS

Lead Author

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yoshinori hayashi

Ph.D

Department of physiology,NUSD,JAPAN

Lead Author

E-mail

tatuo shirota

Ph.D

Department of orofacial surgery, showa university, Japan

Lead Author

E-mail

Koichi Iwata

Nihon University

Lead Author

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Topics

  • Models: Chronic Pain - Neuropathic