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Papers of the Week

Papers: 22 Apr 2023 - 28 Apr 2023

Basic Science

Animal Studies, Molecular/Cellular, Neurobiology, Pharmacology/Drug Development

Neuropathic Pain, Orofacial/Head Pain

2023 Jul

Brain Behav Immun Health



Microglia cause structural remodeling of noradrenergic axon in the trigeminal spinal subnucleus caudalis after infraorbital nerve injury in rats.


Hayashi Y, Otsuji J, Oshima E, Hitomi S, Ni J, Urata K, Shibuta I, Iwata K, Shinoda M


The dysfunction of descending noradrenergic (NAergic) modulation in second-order neurons has long been observed in neuropathic pain. In clinical practice, antidepressants that increase noradrenaline levels in the synaptic cleft are used as first-line agents, although adequate analgesia has not been occasionally achieved. One of the hallmarks of neuropathic pain in the orofacial regions is microglial abnormalities in the trigeminal spinal subnucleus caudalis (Vc). However, until now, the direct interaction between descending NAergic system and Vc microglia in orofacial neuropathic pain has not been explored. We found that reactive microglia ingested the dopamine-β-hydroxylase (DβH)-positive fraction, NAergic fibers, in the Vc after infraorbital nerve injury (IONI). Major histocompatibility complex class I (MHC-I) was upregulated in Vc microglia after IONI. Interferon-γ (IFNγ) was induced in trigeminal ganglion (TG) neurons following IONI, especially in C-fiber neurons, which conveyed to the central terminal of TG neurons. Gene silencing of IFNγ in the TG reduced MHC-I expression in the Vc after IONI. Intracisternal administration of exosomes from IFNγ-stimulated microglia elicited mechanical allodynia and a decrease in DβH in the Vc, which did not occur when exosomal MHC-I was knocked down. Similarly, MHC-I knockdown in Vc microglia attenuated the development of mechanical allodynia and a decrease in DβH in the Vc after IONI. These results show that microglia-derived MHC-I causes a decrease in NAergic fibers, culminating in orofacial neuropathic pain.