Abstract
BackgroundTrigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown.MethodsThe partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing.ResultspIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5−/− mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5−/− mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.ConclusionsCXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.
Highlights
Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome
We found that partial infraorbital nerve ligation (pIONL) increased chemokine C-X-C motif ligand 13 (CXCL13) and chemokine C-X-C motif receptor 5 (CXCR5) expression in trigeminal ganglion (TG) neurons, and CXCL13/ CXCR5 was involved in orofacial mechanical allodynia
PD98059 pretreatment reduced the mRNA level of tumor necrosis factor-α (TNF-α) (1 ± 0.27 vs. 0.27 ± 0.09, vehicle + CXCL13 vs. PD98059 + CXCL13, P < 0.05, Student’s t test) and IL-1β (1 ± 0.23 vs. 0.31 ± 0.06, vehicle + CXCL13 vs. PD98059 + CXCL13, P < 0.05, Student’s t test), which was examined 3 h after CXCL13 injection. These data indicate that CXCL13-induced mechanical allodynia is dependent on CXCR5/extracellular signalregulated kinase (ERK)/TNFα and IL-1β pathway. This is the first study that examines in detail the role of CXCL13/CXCR5 signaling in the maxillary part of the TG in pIONL-induced mechanical allodynia
Summary
Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown. Chronic neuropathic pain of orofacial region resulting from nerve trauma, compression, and/or demyelination is debilitating and often refractory to treatment. Neuroinflammation has been demonstrated to play an important role in the pathogenesis of neuropathic pain [1, 2]. CXCL13 was expressed in the spinal cord of naïve mice and was upregulated after spinal nerve ligation (SNL) [11]. Cxcl mRNA was increased in the dorsal root ganglion (DRG) after DRG local inflammation or peripheral nerve injury [12]
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