Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice

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.

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

“…Proinflammatory cytokines were upregulated in the spinal cord after nerve injury [23]. TNF-α and IL-1β were downstream targets for ERK1/2 signaling pathway in regulating neuropathic pain [24]. We next verified whether TNF-α and IL-1β were involved in the attenuation of CCI induced neuropathic pain which was realized by dezocine.…”

Melatonin‐mediated inhibition of Cav3.2 T‐type Ca2+ channels induces sensory neuronal hypoexcitability through the novel protein kinase C‐eta isoform

“…Complete Freund's adjuvant (CFA, 20 μL) was administered into the left buccal pad area. The mechanical threshold for escape behavior (escape threshold, ET) was measured as previously described . In brief, after the day of CFA injection, the mechanical hypersensitivity was tested by a series of von Frey filaments every day (0.02‐2.56 g, Stoelting, IL, USA).…”

“…Melatonin (1 nmol) or Z941 (2 nmol) was injected from the infraorbital foramen to the foramen rotundum through a needle (30 G). Once the needle tip terminated at the medial part of the mouse trigeminal ganglion, reagents at a volume of 5 μL were slowly delivered …”

Identification of significant gene biomarkers of low back pain caused by changes in the osmotic pressure of nucleus pulposus cells

“…However, the role of CXCL13 in pain was contrary to our expectation. CXCL13 and CXCR5 produce orofacial pain through ERK-mediated proinflammatory cytokines 59 . After ligation of the spinal cord nerve in mice, it was found that CXCL13 was upregulated in the spinal cord, and intrathecal injection of CXCL13 could cause hyperalgesia and activation of astrocytes 60 .…”