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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

pIONL induces mechanical allodynia assessed by orofacial operant test and increases ATF3 expression in the maxillary division of TG neurons. a Total contact number of orofacial operant test with mechanical stimulation was comparable between sham and pIONL mice. P > 0.05. Two-way repeated measures ANOVA. b Total contact time was significantly decreased from 1 to 21 days after pIONL, compared to sham group. **P < 0.01, ***P < 0.001, pIONL vs. sham. Two-way repeated measures ANOVA followed by Bonferroni test. c The percentage of ATF3-positive cells were dramatically increased in the maxillary division (V2) of TG 10 days after pIONL, whereas ATF3-positive cells were not significantly changed in the ophthalmic (V1) division or mandibular (V3) division. ***P < 0.001, pIONL vs. sham. Student’s t test. d–g Representative images show the expression of ATF3 in the TG of sham-treated (d, e) or pIONL (f, g) animals. e, g High-magnification images of d and f, indicated in the white boxes
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Fig1: pIONL induces mechanical allodynia assessed by orofacial operant test and increases ATF3 expression in the maxillary division of TG neurons. a Total contact number of orofacial operant test with mechanical stimulation was comparable between sham and pIONL mice. P > 0.05. Two-way repeated measures ANOVA. b Total contact time was significantly decreased from 1 to 21 days after pIONL, compared to sham group. **P < 0.01, ***P < 0.001, pIONL vs. sham. Two-way repeated measures ANOVA followed by Bonferroni test. c The percentage of ATF3-positive cells were dramatically increased in the maxillary division (V2) of TG 10 days after pIONL, whereas ATF3-positive cells were not significantly changed in the ophthalmic (V1) division or mandibular (V3) division. ***P < 0.001, pIONL vs. sham. Student’s t test. d–g Representative images show the expression of ATF3 in the TG of sham-treated (d, e) or pIONL (f, g) animals. e, g High-magnification images of d and f, indicated in the white boxes

Mentions: Before and after pIONL or sham operation, we performed orofacial operant tests to check mechanical allodynia. Both total contact number and contact time were recorded and analyzed. As shown in Fig. 1a, total contact number was not significantly changed after pIONL, and no significant difference was found between sham and pIONL groups (P > 0.05, two-way repeated measures ANOVA). However, total contact time in pIONL group was reduced 1 day after the operation, maintained from day 3 to day 14, began to recover toward baseline at day 21 and fully recovered at day 28 (P < 0.001, two-way repeated measures ANOVA), whereas the sham-operated animals showed similar contact time during all the time points (P > 0.05, two-way repeated measures ANOVA, Fig. 1b). These data indicate that the reduction of total contact time in pIONL group is not due to the decrease of animals’ attempt to drink milk [23]. In addition, the time course of pIONL-induced mechanical allodynia reflected by the reduction of contact time is comparable to the test by Von Frey filaments [24], suggesting that orofacial operant test is reliable, and pIONL induces persistent mechanical allodynia.Fig. 1


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)

pIONL induces mechanical allodynia assessed by orofacial operant test and increases ATF3 expression in the maxillary division of TG neurons. a Total contact number of orofacial operant test with mechanical stimulation was comparable between sham and pIONL mice. P > 0.05. Two-way repeated measures ANOVA. b Total contact time was significantly decreased from 1 to 21 days after pIONL, compared to sham group. **P < 0.01, ***P < 0.001, pIONL vs. sham. Two-way repeated measures ANOVA followed by Bonferroni test. c The percentage of ATF3-positive cells were dramatically increased in the maxillary division (V2) of TG 10 days after pIONL, whereas ATF3-positive cells were not significantly changed in the ophthalmic (V1) division or mandibular (V3) division. ***P < 0.001, pIONL vs. sham. Student’s t test. d–g Representative images show the expression of ATF3 in the TG of sham-treated (d, e) or pIONL (f, g) animals. e, g High-magnification images of d and f, indicated in the white boxes
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Fig1: pIONL induces mechanical allodynia assessed by orofacial operant test and increases ATF3 expression in the maxillary division of TG neurons. a Total contact number of orofacial operant test with mechanical stimulation was comparable between sham and pIONL mice. P > 0.05. Two-way repeated measures ANOVA. b Total contact time was significantly decreased from 1 to 21 days after pIONL, compared to sham group. **P < 0.01, ***P < 0.001, pIONL vs. sham. Two-way repeated measures ANOVA followed by Bonferroni test. c The percentage of ATF3-positive cells were dramatically increased in the maxillary division (V2) of TG 10 days after pIONL, whereas ATF3-positive cells were not significantly changed in the ophthalmic (V1) division or mandibular (V3) division. ***P < 0.001, pIONL vs. sham. Student’s t test. d–g Representative images show the expression of ATF3 in the TG of sham-treated (d, e) or pIONL (f, g) animals. e, g High-magnification images of d and f, indicated in the white boxes
Mentions: Before and after pIONL or sham operation, we performed orofacial operant tests to check mechanical allodynia. Both total contact number and contact time were recorded and analyzed. As shown in Fig. 1a, total contact number was not significantly changed after pIONL, and no significant difference was found between sham and pIONL groups (P > 0.05, two-way repeated measures ANOVA). However, total contact time in pIONL group was reduced 1 day after the operation, maintained from day 3 to day 14, began to recover toward baseline at day 21 and fully recovered at day 28 (P < 0.001, two-way repeated measures ANOVA), whereas the sham-operated animals showed similar contact time during all the time points (P > 0.05, two-way repeated measures ANOVA, Fig. 1b). These data indicate that the reduction of total contact time in pIONL group is not due to the decrease of animals’ attempt to drink milk [23]. In addition, the time course of pIONL-induced mechanical allodynia reflected by the reduction of contact time is comparable to the test by Von Frey filaments [24], suggesting that orofacial operant test is reliable, and pIONL induces persistent mechanical allodynia.Fig. 1

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