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. 2013 Mar 22:9:13.
doi: 10.1186/1744-8069-9-13.

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

Jian-Qiao Fang  1 , Jun-Ying Du, Yi Liang, Jun-Fan Fang
Affiliations

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

Jian-Qiao Fang et al. Mol Pain. .

Abstract

Background: Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain.

Results: EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat's paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression.

Conclusions: The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats.

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Figures

Figure 1
Figure 1
Behavioral test of rats in each group at different time-point. A. Ipsilateral percent swelling of the paw of rats in each group at different time-point. The percent swelling of the paw was assessed by using plethymometer and water displacement method. The percent swelling of the paw was measured pre-injection and on day 1, 3, 7, 14 and 21 after saline/CFA injection. All data are expressed as means±SEM, n=12. **P<0.01 vs. group Control. ▲ ▲ P<0.01 vs. group CFA. ● P<0.05, ● ● P<0.01 vs. group CFA+Sham EA. B. Ipsilateral paw withdrawal thresholds (PWTs) of rats in each group at different time-point. PWTs were assessed by using dynamic plantar aesthesiometer. PWTs were measured pre-injection and on day 1, 3, 7, 14 and 21 after saline/CFA injection. All data are expressed as means±SEM, n=12. **P<0.01 vs. group Control. ▲ ▲ P<0.01 vs. group CFA. ● ● P<0.01 vs. group CFA+Sham EA.
Figure 2
Figure 2
CFA induces p38 MAPK activation in the ipsilateral spinal cord dorsal horn at different time-point. A-E. Immunohistochemistry shows p-p38 MAPK IR cells in the L4-6 ipsilateral spinal cord dorsal horn of Control rats (A), CFA rats at 3 d (B), 7 d (C), 14 d (D) and 21 d (E). F. Quantification of p-p38MAPK IR shows that CFA induces p-p38 MAPK IR cells expression in the L4-6 ipsilateral spinal cord dorsal horn after day 3–14. **P<0.01 vs. group Control, n=3-5. All data are expressed as means±SEM. Scale bars: 100 μm, section thickness: 30 μm.
Figure 3
Figure 3
Phosphor-ATF-2 IR cells expression in the Ipsilateral spinal cord dorsal horn in CFA rats at different time-point. A-E. Immunohistochemistry shows p-ATF-2 IR cells in the L4-6 ipsilateral spinal cord dorsal horn of Control rats (A), CFA rats at 3 d (B), 7 d (C), 14 d (D) and 21 d (E) after CFA injection. F. Quantification of p-ATF-2 IR shows that CFA induces p-ATF-2 IR cells expression in the L4-6 ipsilateral spinal cord dorsal horn after day 3–14. **P<0.01 vs. group Control, n=3-5, All data are expressed as means±SEM. Scale bars: 100 μm, section thickness: 30 μm.
Figure 4
Figure 4
Effect of EA on p-p38MAPK expression in the ipsilateral spinal dorsal horn at 14 day after CFA injection. A-E. Immunohistochemistry shows p-p38 MAPK IR cells in the L4-6 ipsilateral spinal cord dorsal horn of Control rats (A), CFA rats (B), CFA+EA rats (C) and CFA+Sham EA rats (D) at 14 day after CFA injection. E. Quantification of p-p38 MAPK IR shows that EA suppresses p-p38 MAPK IR cells in the L4-6 ipsilateral spinal dorsal horn at 14 day after CFA injection. **P<0.01 vs. group Control. ▲ ▲ P<0.01 vs. group CFA. ● ● P<0.01 vs. group CFA+Sham EA. n=3-5. Scale bars: 100 μm, section thickness: 30 μm. F, G. Western blotting analysis reveals that EA suppresses p-p38 MAPK protein in the L4-6 ipsilateral spinal dorsal horn at 14 day after CFA injection. G. Quantification of F. p-p38 MAPK protein in normalized against β-actin. n=4-6, **P<0.01 vs. group Control. ▲ P<0.05 vs. group CFA. ● P<0.05 vs. group CFA+Sham EA.
Figure 5
Figure 5
Effect of EA on p-ATF-2 expression in the ipsilateral spinal dorsal horn at 14 day after CFA injection. A-E. Immunohistochemistry shows p-ATF-2 IR cells in the L4-6 ipsilateral spinal cord dorsal horn of Control rats (A), CFA rats (B), CFA+EA rats (C) and CFA+Sham EA rats (D) at 14 day after CFA injection. F. Quantification of p-ATF-2 IR shows that EA suppresses p-ATF-2 IR cells in the L4-6 ipsilateral spinal dorsal horn on 14 day after CFA injection. **P<0.01 vs. group Control. ▲ ▲ P<0.01 vs. group CFA. ● ● P<0.01 vs. group CFA+Sham EA. n=3-5. Scale bars: 100 μm, section thickness: 30 μm. F, G. Western blotting analysis reveals that EA suppresses p-ATF-2 protein in the L4-6 ipsilateral spinal dorsal horn at 14 day after CFA injection. F. Quantification of G. p-ATF-2 protein in normalized against β-actin. n=4-6, *P<0.05, **P<0.01 vs. group Control. ▲ P<0.05 vs. group CFA. ● P<0.05 vs. group CFA+Sham EA.
Figure 6
Figure 6
Effect of EA on COX-2 expression in the ipsilateral spinal dorsal horn at 14 day after CFA injection. A. Expression of COX-2 mRNA (relative to GAPDH) in L4-6 ipsilateral spinal cord dorsal horn measured by qPCR. Standard curve of COX-2 and GAPDH mRNA in the ipsilateral spinal cord dorsal horn is shown in Additional file 1: Figure S3. It shows that relative quantity of COX-2 mRNA has no significant difference among Control group, CFA group, CFA+EA group and CFA+Sham EA group on day 14 after CFA injection. n=5-7. B, C. Western blotting analysis reveals that COX-2 protein in the L4-6 ipsilateral spinal dorsal horn has also no significant difference among Control group, CFA group, CFA+EA group and CFA+Sham EA group on 14 day after CFA injection. C. Quantification of B. COX-2 protein in normalized against β-actin. n=4-6.
Figure 7
Figure 7
Effect of EA on VR-1 expression in the ipsilateral spinal dorsal horn at 14 day after CFA injection. A. Expression of VR-1 mRNA (relative to GAPDH) in L4-6 ipsilateral spinal dorsal horn measured by qPCR. Standard curve of VR-1 and GAPDH mRNA in the ipsilateral spinal dorsal horn is shown in Additional file 1: Figure S4. It shows that relative quantity of VR-1 mRNA of CFA group is much more than that of Control group on day 14 after CFA injection, and EA suppresses the expression of VR-1 mRNA. *P<0.05 vs. group Control. ▲ ▲ P<0.01 vs. group CFA. ● P<0.05 vs. group CFA+Sham EA. n=5-7. B, C. Western blotting analysis reveals that VR-1 protein in the L4-6 ipsilateral spinal cord dorsal horn has significant difference between Control group and CFA group, and EA suppresses the expression of VR-1 protein. C. Quantification of B. VR-1 protein in normalized against β-actin. *P<0.05, **P<0.01vs. group Control. ▲ P<0.05 vs. group CFA. n=4-6.
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