Electroacupuncture Confers Antinociceptive Effects via Inhibition of Glutamate Transporter Downregulation in Complete Freund's Adjuvant-Injected Rats

Abstract

When we evaluated changes of glial fibrillary acidic protein (GFAP) and two glutamate transporter (GTs) by immunohistochemistry, expression of GFAP showed a significant increase in complete Freund's adjuvant (CFA)-injected rats; however, this expression was strongly inhibited by electroacupuncture (EA) stimulation. Robust downregulation of glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) was observed in CFA-injected rats; however, EA stimulation resulted in recovery of this expression. Double-labeling staining showed co-localization of a large proportion of GLAST or GLT-1 with GFAP. Using Western blot, we confirmed protein expression of two GTs, but no differences in the mRNA content of these GTs were observed. Because EA treatment resulted in strong inhibition of CFA-induced proteasome activities, we examined the question of whether thermal sensitivities and GTs expression could be regulated by proteasome inhibitor MG132. CFA-injected rats co-treated with EA and MG132 showed a significantly longer thermal sensitivity, compared with CFA-injected rats with or without MG132. Both EA and MG132 blocked CFA-induced GLAST and GLT-1 downregulation within the spinal cord. These results provide evidence for involvement of GLAST and GLT-1 in response to activation of spinal astrocytes in an EA antinociceptive effect. Antinociceptive effect of EA may be induced via proteasome-mediated regulation of spinal GTs.

Spatiotemporal changes of optical signals in the somatosensory cortex of neuropathic rats after electroacupuncture stimulation

“…Multiple lines of evidence on EA-induced analgesia suggest that EA stimulation mediates the release of neurotransmitters at several sites in the CNS. EA studies have investigated the mechanisms of analgesic effects of EA stimulation and showed involvement of opioids [37], norepinephrine [38], serotonin [39], glutamate and its receptors [40, 41], glial cells [42], and cytokines [36] in both peripheral and spinal sites. Overall, EA-induced bioactive chemicals are involved in the inhibition of neuropathic pain [43].…”

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

“…12,69 Multiple studies have demonstrated that dysfunctional glial GTs are critically implicated in the genesis of pathological pain. The down regulation of glial GT expression in the SDH is found in animals with neuropathic pain induced by chronic constriction nerve injury, 13 partial sciatic nerve ligation, 25,70 spinal cord injury, 71 chemotherapy (paclitaxel), 29,72 animals with inflammatory pain induced by complete Freund’s adjuvant, 73 and animals with morphine tolerance. 74,75 We have shown that deficient glial glutamate uptake enhances activation of AMPA and NMDA receptors, and causes glutamate to spill into the extrasynaptic space and activate extrasynaptic NMDA receptors in spinal sensory neurons.…”

“…The posttranslational mechanisms that reduce glial GT functions in the SDH include: nitration of glial GTs 78 in rats with chemotherapy induced pain, 78 proteasome-mediated degradation of the glutamate aspartate transporter and GLT-1 proteins in rats with inflammatory pain induced by complete Freund’s adjuvant, 73 and endocytosis of the glutamate aspartate transporter and GLT-1 from the cell surface into the cytosol in rats with neuropathic pain 14 and morphine tolerance. 79 We also showed that the endocytosis of glial GTs in neuropathic pain is induced by endogenous IL-1β and activation of protein kinase C. 14 Our current study demonstrated that AMPK is another molecule involving in the signaling pathways regulating trafficking of glial GTs in the spinal cord.…”

Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain

“…Moreover, two Hz electroacupuncture at ST36 and Sanyinjiao (SP6) once a day for three days significantly increased PWL and inhibited CFA-induced upregulation of glial fibrillary acidic protein, an astrocyte marker. 98 It also reversed CFA-caused downregulation of glutamate-aspartate transporter and glutamate transporter-1 in astrocytes. Concomitantly, proteasome inhibitor MG132 treatment significantly increased PWL and reversed CFA-induced downregulation of glutamate-aspartate transporter and glutamate transporter-1.…”