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Electroacupuncture Alleviates Retrieval of Pain Memory and Its Effect on Phosphorylation of cAMP Response Element-Binding Protein in Anterior Cingulate Cortex in Rats

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Electroacupuncture Alleviates Retrieval of Pain Memory and Its Effect on Phosphorylation of cAMP Response Element-Binding Protein in Anterior Cingulate Cortex in Rats

Jing Sun et al. Behav Brain Funct.

Abstract

Background: Recent evidence suggests that persistent pain and recurrent pain are due to the pain memory which is related to the phosphorylation of cAMP response element-binding protein (p-CREB) in anterior cingulate cortex (ACC). Eletroacupuncture (EA), as a complementary Chinese medical procedure, has a significant impact on the treatment of pain and is now considered as a mind-body therapy.

Methods: The rat model of pain memory was induced by two injections of carrageenan into the paws, which was administered separately by a 14-day interval, and treated with EA therapy. The paw withdrawal thresholds (PWTs) of animals were measured and p-CREB expressions in ACC were detected by using immunofluorescence (IF) and electrophoretic mobility shift assay (EMSA). Statistical comparisons among different groups were made by one-way, repeated-measures analysis of variance (ANOVA).

Results: The second injection of carrageenan caused the decrease of PWTs in the non-injected hind paw. EA stimulation applied prior to the second injection, increased the values of PWTs. In ACC, the numbers of p-CREB positive cells were significantly increased in pain memory model rats, which were significantly reduced by EA. EMSA results showed EA also down-regulated the combining capacity of p-CREB with its DNA. Furthermore, the co-expression of p-CREB with GFAP, OX-42, or NeuN in ACC was strengthened in the pain memory model rats. EA inhibited the co-expression of p-CREB with GFAP or OX-42, but not NeuN in ACC.

Conclusions: The present results suggest the retrieval of pain memory could be alleviated by the pre-treatment of EA, which is at least partially attributed to the down-regulated expression and combining capacity of p-CREB and the decreased expression of p-CREB in astrocytes and microglia cells.

Figures

Figure 1
Figure 1
Mechanical allodynia of rats in repetitive-crossover carrageenan injection with a 2-week interval. Rats of each group were tested for mechanical allodynia of bilateral hind paws at time points of before (Base), and 4 h, 24 h, 48 h, 72 h after carrageenan-injection. The first injection was administered into the plantar surface of the right paw (a and b); the second injection was administered into the left paw 2 weeks later (c and d). The results showed a sustained decrease of mechanical threshold in the initial injected paw (d). Error bars indicated standard error of the mean. Ten rats for each group. ** p < 0.01, vs. the control group; # p < 0.05, ## p < 0.01, vs. the model group.
Figure 2
Figure 2
Phosphorylation of CREB in the anterior cingulate cortex (ACC). Differences in p-CREB expressions in control, model, and EA groups were presented in figure a, b, and c. Yellow line in figure a indicated the selected field in which the numbers of p-CREB-positive cells were counted. The left ACC in the harvested brain cortex was circled with a yellow line in figure d. Quantification of p-CREB positive cells was shown in figure e. Error bars indicated standard error of the mean. Three rats for each group, five slides for each rat. ** p < 0.01, vs. the control group; ## p < 0.01, vs. the model group.
Figure 3
Figure 3
Binding activity of p-CREB in nuclear extracts assessed by EMSA. The part a showed the excess of unlabeled p-CREB probes and unlabeled mutational p-CREB probes abolished binding, demonstrating the specificity of all binding complexes. Binding activity of p-CREB among the control, model, and EA groups was shown in the part b. Arrows indicated the binding of p-CREB and the free probe.
Figure 4
Figure 4
Co-localization of p-CREB and GFAP in coronal brain sections of ACC. Photomicrographs showed the expression of p-CREB (red) and GFAP (an astrocytic marker, green) from the same sections in figure a. Figure b was a high magnification image of the areas indicated by the yellow squares in the figure a. The double-immunofluorescence labeling showed that p-CREB co-expressed with GFAP in the ACC. Numbers of GFAP-positive cells and co-localization of p-CREB with GFAP were analysed in figure c and d. Error bars indicated standard error of the mean. Four rats for each group, five slides for each rat. * p < 0.05, ** p < 0.01 vs. the control group; ## p < 0.01 vs. the model group.
Figure 5
Figure 5
Co-localization of p-CREB and OX-42 in coronal brain sections of ACC. Photomicrographs showed the expression of p-CREB (red) and OX-42 (a microglial marker, green) from the same sections in figure a. Figure b was a high magnification image of the areas indicated by the yellow squares in the figure a. The double-immunofluorescence labeling showed that p-CREB co-expressed with OX-42 in the ACC. Numbers of OX-42-positive cells and co-localization of p-CREB with OX-42 were analysed in figure c and d. Error bars indicated standard error of the mean. Four rats for each group, five slides for each rat. * p < 0.05 vs. the control group.
Figure 6
Figure 6
Co-localization of p-CREB and NeuN in coronal brain sections of ACC. Photomicrographs showed the expression of p-CREB (red) and NeuN (a neuronal marker, green) from the same sections in figure a. Figure b was a high magnification image of the areas indicated by the yellow squares in the figure a. The double-immunofluorescence labeling showed that p-CREB co-expressed with NeuN in the ACC. Numbers of NeuN-positive cells and co-localization of p-CREB with NeuN were analysed in figure c and d. Error bars indicated standard error of the mean. Four rats for each group, five slides for each rat. * p < 0.05 vs. the control group.

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