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

Abstract

Pain memory is considered as endopathic factor underlying stubborn chronic pain. Our previous study demonstrated that electroacupuncture (EA) can alleviate retrieval of pain memory. This study was designed to observe the different effects between EA and indomethacin (a kind of nonsteroid anti-inflammatory drugs, NSAIDs) in a rat pain memory model. To explore the critical role of protein kinase A (PKA) in pain memory, a PKA inhibitor was microinjected into anterior cingulate cortex (ACC) in model rats. We further investigated the roles of the cyclic adenosine monophosphate (cAMP), PKA, cAMP response element-binding protein (CREB), and cAMP/PKA/CREB pathway in pain memory to explore the potential molecular mechanism. The results showed that EA alleviates the retrieval of pain memory while indomethacin failed. Intra-ACC microinjection of a PKA inhibitor blocked the occurrence of pain memory. EA reduced the activation of cAMP, PKA, and CREB and the coexpression levels of cAMP/PKA and PKA/CREB in the ACC of pain memory model rats, but indomethacin failed. The present findings identified a critical role of PKA in ACC in retrieval of pain memory. We propose that the proper mechanism of EA on pain memory is possibly due to the partial inhibition of cAMP/PKA/CREB signaling pathway by EA.

The Effect of Electroacupuncture on PKMzeta in the ACC in Regulating Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain

“…Regarding EA analgesia and its mechanism in treating inflammatory pain, several studies have focused on the analgesic effect of EA on the sensory-discriminative aspect of pain [ 18 – 21 ]; however, few studies have examined the effect and mechanisms of EA on the emotional-affective dimension of pain. A growing number of studies have indicated that EA can relieve pain-related anxiety [ 13 , 14 ] through a mechanism that involves opioid receptor activation in the ACC [ 32 ]. However, the mechanisms underlying the effects of EA on inflammatory pain-related anxiety are not completely understood.…”

“…In recent years, the mechanism and treatment of psychiatric disorders associated with chronic pain have received increasing attention. Previous studies by our laboratory and others have reported that EA can significantly reduce the anxiety-like behaviors associated with chronic pain [ 13 , 14 ]. However, the mechanism for these effects is unclear.…”

Pain aversion and anxiety-like behavior occur at different times during the course of chronic inflammatory pain in rats

“… 7 – 9 Recently, a significant number of preclinical research groups have focused their attention on the affective symptoms of pain. 10 – 12 The conditioned-place aversion (CPA) paradigm is a highly sensitive method for measuring the negative effect of an aversive memory associated with a pain-paired context. 13 – 16 Recent studies have shown that the affective component of chronic inflammatory pain can be assessed with a CPA test (pain aversion) and other emotional behavior tests, such as the elevated zero maze (EZM) and open field (OF) tests.…”

Determining 5HT7R’s involvement in modifying the antihyperalgesic effects of electroacupuncture on rats with recurrent migraine

“…However, how EA regulates 5-HT 7 R remains unclear. Electroacupuncture was reported to reduce the cytoplasmic content of cAMP [26]. Decreased cAMP affects the phosphorylation of PKA and ERK 1/2 [71,72].…”

“…Our previous investigation found EA shows a direct effect on nociceptive neurons [23,24]. In addition, several studies [25][26][27] suggested PKA and ERK 1/2 in the spinal dorsal horn might involve EA antihyperalgesia.…”