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

Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ - J Neuroinflammation (2016)

Bottom Line: The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG.Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL.Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.

View Article: PubMed Central - PubMed

Affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Seyuan Road, Nantong, Jiangsu, 226019, China.

ABSTRACT

Background: 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.

Methods: The 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.

Results: pIONL 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.

Conclusions: CXCL13 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.

No MeSH data available.


Related in: MedlinePlus

CXCR5 is essential for pIONL-induced mechanical allodynia. a Mechanical sensitivity assessed by Von Frey test was indistinguishable in WT and KO mice. b pIONL-induced mechanical allodynia was significantly reduced in Cxcr5 KO mice, compared to WT mice. *P < 0.05, **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. c Pretreatment with LV-Cxcr5 shRNA increased the contact time between 3 and 21 days after the operation, compared to LV-NC-injected mice. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. d Posttreatment with LV-Cxcr5 shRNA increased the contact time between 7 and 21 days after the operation, compared to LV-NC treatment. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. e Real-time PCR assay of Cxcr5 shows that pretreatment with LV-Cxcr5 shRNA inhibited pIONL-induced Cxcr5 upregulation. *P < 0.05, **P < 0.01, ***P < 0.001. Student’s t test
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4940825&req=5

Fig5: CXCR5 is essential for pIONL-induced mechanical allodynia. a Mechanical sensitivity assessed by Von Frey test was indistinguishable in WT and KO mice. b pIONL-induced mechanical allodynia was significantly reduced in Cxcr5 KO mice, compared to WT mice. *P < 0.05, **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. c Pretreatment with LV-Cxcr5 shRNA increased the contact time between 3 and 21 days after the operation, compared to LV-NC-injected mice. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. d Posttreatment with LV-Cxcr5 shRNA increased the contact time between 7 and 21 days after the operation, compared to LV-NC treatment. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. e Real-time PCR assay of Cxcr5 shows that pretreatment with LV-Cxcr5 shRNA inhibited pIONL-induced Cxcr5 upregulation. *P < 0.05, **P < 0.01, ***P < 0.001. Student’s t test

Mentions: To determine the role of CXCR5 in trigeminal neuropathic pain, we checked pain behaviors in wild-type (WT; C57Bl/6) mice and Cxcr5−/− (KO) mice. Acute mechanical sensitivity, as evaluated by Von Frey filament (Fig. 5a) was comparable between the two genotypes (P > 0.05, Student’s t test). We then tested mechanical allodynia by orofacial operant behavioral assessment after pIONL. pIONL-induced mechanical allodynia was significantly reduced at days 3, 7, 10, and 14 in Cxcr5 KO mice compared to WT mice (P < 0.001, two-way repeated measures ANOVA, Fig. 5b)Fig. 5


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

Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ - J Neuroinflammation (2016)

CXCR5 is essential for pIONL-induced mechanical allodynia. a Mechanical sensitivity assessed by Von Frey test was indistinguishable in WT and KO mice. b pIONL-induced mechanical allodynia was significantly reduced in Cxcr5 KO mice, compared to WT mice. *P < 0.05, **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. c Pretreatment with LV-Cxcr5 shRNA increased the contact time between 3 and 21 days after the operation, compared to LV-NC-injected mice. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. d Posttreatment with LV-Cxcr5 shRNA increased the contact time between 7 and 21 days after the operation, compared to LV-NC treatment. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. e Real-time PCR assay of Cxcr5 shows that pretreatment with LV-Cxcr5 shRNA inhibited pIONL-induced Cxcr5 upregulation. *P < 0.05, **P < 0.01, ***P < 0.001. Student’s t test
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940825&req=5

Fig5: CXCR5 is essential for pIONL-induced mechanical allodynia. a Mechanical sensitivity assessed by Von Frey test was indistinguishable in WT and KO mice. b pIONL-induced mechanical allodynia was significantly reduced in Cxcr5 KO mice, compared to WT mice. *P < 0.05, **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. c Pretreatment with LV-Cxcr5 shRNA increased the contact time between 3 and 21 days after the operation, compared to LV-NC-injected mice. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. d Posttreatment with LV-Cxcr5 shRNA increased the contact time between 7 and 21 days after the operation, compared to LV-NC treatment. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. e Real-time PCR assay of Cxcr5 shows that pretreatment with LV-Cxcr5 shRNA inhibited pIONL-induced Cxcr5 upregulation. *P < 0.05, **P < 0.01, ***P < 0.001. Student’s t test
Mentions: To determine the role of CXCR5 in trigeminal neuropathic pain, we checked pain behaviors in wild-type (WT; C57Bl/6) mice and Cxcr5−/− (KO) mice. Acute mechanical sensitivity, as evaluated by Von Frey filament (Fig. 5a) was comparable between the two genotypes (P > 0.05, Student’s t test). We then tested mechanical allodynia by orofacial operant behavioral assessment after pIONL. pIONL-induced mechanical allodynia was significantly reduced at days 3, 7, 10, and 14 in Cxcr5 KO mice compared to WT mice (P < 0.001, two-way repeated measures ANOVA, Fig. 5b)Fig. 5

Bottom Line: The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG.Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL.Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.

View Article: PubMed Central - PubMed

Affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Seyuan Road, Nantong, Jiangsu, 226019, China.

ABSTRACT

Background: 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.

Methods: The 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.

Results: pIONL 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.

Conclusions: CXCL13 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.

No MeSH data available.


Related in: MedlinePlus