Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 99, Issue -, Pages 266-280Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2021.10.013
Keywords
IL-33; Fyn; GluN2B; Infraorbital nerve injury; Trigeminal spinal subnucleus caudalis; Orofacial neuropathic pain
Categories
Funding
- JSPS KAKENHI [20K09896, 18K09732, 19K10049]
- Sato Fund
- Uemura Fund
- Nihon University Multidisciplinary Research Grant
- Dental Research Center, Nihon University School of Dentistry
- Grants-in-Aid for Scientific Research [18K09732, 19K10049, 20K09896] Funding Source: KAKEN
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The study found that IL-33 plays a crucial role in mechanical allodynia in orofacial neuropathic pain patients, and neutralization of IL-33 can alleviate symptoms. IL-33 induces GluN2B phosphorylation through the Fyn kinase pathway to regulate synaptic transmission.
Orofacial neuropathic pain can cause considerable disruptions in patients' daily lives, especially because of a lack of effective medications as its underlying causative mechanisms are not fully understood. Here, we found neuronspecific expression of the interleukin (IL)-33 receptor in the trigeminal spinal subnucleus caudalis (Vc), distinct from the spinal dorsal horn. Reduction in head withdrawal threshold in response to von Frey filament stimulation of the whisker pad skin was inversely correlated with the upregulation of IL-33 in the Vc after infraorbital nerve injury (IONI). Neutralization of IL-33 in the Vc alleviated mechanical allodynia in the whisker pad skin after IONI; conversely, intracisternal administration of IL-33 elicited mechanical allodynia in the whisker pad skin, which was relieved by GluN2B antagonism. Moreover, IL-33 triggered the potentiation of GluN2B-containing Nmethyl-D-aspartate receptor-mediated synaptic currents and phosphorylation of synaptosomal GluN2B in the Vc, whereas IONI-induced GluN2B phosphorylation was inhibited by neutralization of IL-33 in the Vc. IL-33-induced GluN2B phosphorylation was mediated by phosphorylation of Fyn kinase, and inhibition of the Fyn kinase pathway prevented the development of IL-33-induced mechanical allodynia. Our findings provide insights into a new mechanism by which IL-33 directly regulates synaptic transmission and suggest that IL-33 signaling could be a candidate target for therapeutic interventions for orofacial neuropathic pain.
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