Abstract
Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.
Highlights
Trigeminal nerve injury due to tooth extraction, orofacial trauma, or dental implant displacement is known to cause persistent neuropathic pain in the orofacial region
The mechanical head withdrawal threshold (MHWT) was significantly reduced one day after infraorbital nerve injury (IONI) in saline-administrated rats, and this reduction in MHWT was observed throughout the experimental period
The findings of this study can be summarized as follows: (1) The MHWT was significantly reduced after IONI. (2) The number of c-Fos-IR cells and the fluorescence intensity of ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and C1q were significantly increased in the Vc following IONI. (3) Minocycline administration significantly suppressed the number of c-Fos-IR cells as well as reduced the expression of Iba1 and GFAP. (4) C1q administration caused an increase in the expression of GFAP and promoted mechanical hypersensitivity in naïve rats
Summary
Trigeminal nerve injury due to tooth extraction, orofacial trauma, or dental implant displacement is known to cause persistent neuropathic pain in the orofacial region. Specific inhibitors of microglial and astrocytic activation markedly attenuate the initiation and maintenance phases of neuropathic pain, respectively [3,4]. Pharmacological inhibition or pharmacogenetic ablation of microglia failed to ameliorate the maintenance phase of neuropathic pain [5,6,7]. It has been reported that microglia-derived interleukin (IL)-18 activates astrocytes in the spinal cord, resulting in the occurrence of tactile allodynia [9]. This evidence indicates that microglia–astrocyte communication is required for the development of neuropathic pain in the spinal cord. The involvement of microglia–astrocyte communication in orofacial neuropathic pain remains unknown
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