<p>Electroacupuncture Regulates Pain Transition by Inhibiting the mGluR5-PKCϵ Signaling Pathway in the Dorsal Root Ganglia</p>

Abstract

Background: Acute pain can transition to chronic pain, presenting a major clinical challenge. Electroacupuncture (EA) can partly prevent the transition from acute to chronic pain. However, little is known about the mechanisms underlying the effect of EA. This study investigated the effect of EA on pain transition and the activation of metabotropic glutamate receptor 5 (mGluR5)-protein kinase C epsilon (PKCε) signaling pathway in the dorsal root ganglia (DRG). Methods: The hyperalgesic priming model was established by the sequential intraplantar injection of carrageenan (1%, 100 μL) and prostaglandin E2 (PGE2) into the left hind paw of rats. EA treatment (2/100 Hz, 30 min, once/day) was applied at bilateral Zusanli (ST36) and Kunlun (BL60) acupoints in rats. Von Frey filaments were used to investigate the mechanical withdrawal threshold (MWT) at different time points. The protein expression levels of mGluR5 and PKCε in the ipsilateral L4-L6 DRGs of rats were detected by Western blot. Some pharmacological experiments were performed to evaluate the relationship between mGluR5, PKCε and the MWT. It was also used to test the effects of EA on the expression levels of mGluR5 and PKCε and changes in the MWT. Results: Sequential injection of carrageenan and PGE2 significantly decreased the MWT of rats and up-regulated the expression level of mGluR5 and PKCε in the ipsilateral L4-L6 DRGs. EA can reverse the hyperalgesic priming induced by sequential injection of carrageenan/PGE and down-regulate the protein expression of mGluR5 and PKCε. Glutamate injection instead of PGE2 can mimic the hyperalgesic priming model. Pharmacological blocking of mGluR5 with specific antagonist MTEP can prevent the hyperalgesic priming and inhibit the activation of PKCε in DRGs. Furthermore, EA also produced analgesic effect on the hyperalgesic priming rats induced by carrageenan/mGluR5 injection and inhibited the high expression of PKCε. Sham EA produced none analgesic and regulatory effect. Conclusion: EA can regulate pain transition and it may relate with its inhibitory effect on the activation of mGluR5-PKCε signaling pathway in the DRGs.

Role of GABAAR in the Transition From Acute to Chronic Pain and the Analgesic Effect of Electroacupuncture on Hyperalgesic Priming Model Rats

“…However, there are few reports on whether EA regulates GABAAR expression or function in the peripheral nervous system. Here, we observed that EA treatment significantly prevented the prolonged hyperalgesia induced by PGE 2 injection following Car and decreased the expression of PKCε in the L4-L6 DRGs of hyperalgesic priming model rats, which is consistent with our previous report (Wang et al, 2020). Furthermore, EA upregulated the expression of GABAAR in the L4-L6 DRGs of hyperalgesic priming model rats.…”

“…PKCεV1-2 (a specific PKCε antagonist) was intraplantarly injected into the ipsilateral paws of hyperalgesic priming model rats 10 min before the 2nd injection. PKCεV1-2 significantly inhibited the pain transition induced by Car/PGE 2 injection (Figure 3F, P < 0.05), which is consistent with previous studies (Wang et al, 2020). However, it failed to regulate the expression of GABAAR in the ipsilateral L4-L6 DRGs (Figure 3G, P > 0.05) but successfully inhibited the expression of PKCε (Figure 3G, P < 0.01).…”

“…EA is a form of acupuncture and is widely used to treat various types of pain (Fang et al, 2018;Ali et al, 2020). Previous studies have proven that EA can prevent the induction of pain transition and that its effect is most likely achieved through a PKCε-related pathway (Wang et al, 2020). Previous studies have indicated that upregulation of the expression of GABAAR in the central nervous system is related to the analgesic effect of EA (Jiang et al, 2018;Zheng et al, 2020).…”

“…Numerous primary nociceptive neurons aggregate in the DRG, receive pain signals from the surroundings and play a key role in pain modulation and transmission (Miller et al, 2009;Matsuka et al, 2020). It is known that DRG neurons are responsible for the transition from acute to chronic pain, and the activation of PKCε in DRG neurons plays a key role in hyperalgesic priming type I (Araldi et al, 2019;Wang et al, 2020). However, the other mechanisms underlying pain transition are unknown; specifically, it is unclear whether the inhibitory receptors involved in pain modulation and transmission in the peripheral nervous system contribute to pain transition.…”

“…Electroacupuncture (EA), an effective analgesic method, has been widely used for clinical control of pain and scientific research on this condition (Xiang et al, 2019;Heo et al, 2021). Our previous research has proven that EA can interfere with the transition from acute pain to chronic pain (Wang et al, 2018(Wang et al, , 2020. However, the mechanism underlying the effect of EA on the transition from acute to chronic pain is not yet understood clearly.…”