Electroacupuncture alleviates retrieval of pain memory and its effect on phosphorylation of cAMP response element-binding protein in anterior cingulate cortex in rats

Abstract

BackgroundRecent 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.MethodsThe 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).ResultsThe 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.ConclusionsThe 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.

Inhibition of the cAMP/PKA/CREB Pathway Contributes to the Analgesic Effects of Electroacupuncture in the Anterior Cingulate Cortex in a Rat Pain Memory Model

“…Animal Ltd., Shanghai, China) weighing 180–200 g (6 weeks) were kept at a controlled room temperature (22°C) with a 12-h light-dark cycle and free access to rodent chow and water. All animal experiments were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals [21, 23]. …”

“…As described previously [21], the pain memory model induced by two injections of carrageenan was selected to complete the study. The first carrageenan injection was placed into the left hind paw plantar surface via the subcutaneous injection of 0.1 mL of 2% carrageenan (Sigma Chemical Co, St. Louis, MO, USA) to induce acute inflammatory pain.…”

“…The ACC is an area that encodes pain averseness, thus contributing to pain modulation [19, 20]. As we discovered in a previous study, the phosphorylation of CREB (p-CREB) results in a profound increase in pain memory in the ACC [21]. Thus, we assume that the pathway in pain memory induces a gradual activation of cAMP, PKA, and CREB after nociceptive stimulation in the ACC and that longer lasting forms of latent long-term central sensitization promote long-term memory formation through the cAMP/PKA/CREB signaling pathway.…”

“…Electroacupuncture (EA), a type of acupuncture with electronic stimulation, is widely applied as analgesic for chronic pain in clinical settings. Our previous work has indicated that EA treatment can alleviate the retrieval of pain memory [21]. Although some of the pain modulation mechanisms of the analgesic effects of EA and indomethacin have been demonstrated, their potential mechanisms underlying pain memory remain unclear.…”

“…In this study, we established an animal pain memory model using two injections of carrageenan [21, 22]. Animals were treated with EA and indomethacin to study the different effects and explore the mechanism of EA on pain memory.…”