Synergistic antinociceptive effects of N-methyl-D-aspartate receptor antagonist and electroacupuncture in the complete Freund's adjuvant-induced pain model

Abstract

Abstract. This study examined the synergistic antinociceptive effects associated with signaling pathway proteins of the spinal cord in a complete Freund's adjuvant (CFA)-induced pain model when electroacupuncture (EA) and a N-methyl-D-aspartate receptor (NMDAR) antagonist were administered in combination. EA stimulation (2 Hz, 1 mA) was needledelivered for 20 min once daily at acupoints corresponding to Zusanli and Sanyinjiao with intrathecal injection of the NMDAR antagonist dizocilpine (MK801). Thermal sensitivity of the hindpaw induced by CFA was strongly inhibited by dizocilpine injection and EA stimulation. Co-treatment with EA and dizocilpine showed a synergistic antinociceptive effect against inflammatory pain. On day two of the experiment, we examined the phosphorylation of the NMDAR NR2B subunit, of the extracellular signal-regulated kinase (ERK), p38 and of the cAMP response element-binding protein (CREB) in the ipsilateral dorsal horn of L4-5 segments by Western blot analysis. Phosphorylation of the NMDAR NR2B subunit induced by CFA was markedly inhibited by co-treatment with dizocilpine and EA, but not by dizocilpine or EA treatment alone. CFA-induced phosphorylation of the ERK was inhibited by both dizocilpine and EA, but that of p38 was inhibited by EA only. CFA-induced phosphorylation of CREB was inhibited by dizocilpine, but did not show marked changes. Immunohistochemical analyses confirmed that there was a significant difference in the NMDAR NR2B subunit and ERK phosphorylation. It is possible that the combined treatment with EA and the NMDAR antagonist dizocilpine resulted in synergistic antinociceptive effects in an inflammatory pain model via the inactivation of both the NMDAR NR2B subunit and ERK of the spinal cord.

Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain

“…88,89 The data from these studies once again provide a rationale for pain management and control that combine Western medicine and acupuncture, and they corroborate previously reported data: for example, etoricoxib plus acupuncture has been shown to be more effective than etoricoxib with sham acupuncture or etoricoxib alone for the treatment of knee osteoarthritis pain. 90 …”

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

“…In the central nervous system, EA induces an analgesic response mainly through diverse signal molecules including opioid peptides, glutamate, 5-hydroxytryptamine, and cholecystokinin octapeptide [19, 24]. Many studies investigated that EA stimulation markedly reduces inflammatory hyperalgesia by the inhibition of the release of glutamate and the expression of ERK, p38 in the spinal dorsal horn [10, 11, 24]. Induction of EA antinociception involves N-Methyl-D-aspartate receptor-related signaling and its regulation of calcium influx [25–27].…”

“…Under peripheral inflammation or injury, glial cells such as microglia and astrocytes have an important role in mediation of development and maintenance of central sensitization [11–14]. In particular, astrocytes, the most dominant cells in the central nervous system, play an essential role in pain modulation through rapid removal of glutamate from the synaptic cleft by GTs [2, 8, 15].…”

Effect of Repeated Electroacupuncture Intervention on Hippocampal ERK and p38MAPK Signaling in Neuropathic Pain Rats

“…For example, in depression model rats, EA could reverse CUS induced considerable upregulation of p-ERK expression, ratio of p-ERK1/2 to ERK1/2 and the ratio of p-CREB to CREB in the hippocampus [ 47 ], or enhanced the activation of hippocampal ERK signaling pathway [ 48 ], suggesting an involvement of hippocampal ERK–CREB signaling in EAS-induced antidepressant-like effects. At the spinal level, EAS could suppress complete Freund's adjuvant- (CFA-) induced activation or phosphorylation of p38MAPK in rats with inflammatory pain [ 49 , 50 ]. In contusion injury induced below-level neuropathic pain rats, acupuncture stimulation of Shuigou (GV26) and Yanglingquan (GB34) relieved mechanical allodynia and thermal hyperalgesia and simultaneously inhibited neuropathic pain induced activation of p38MAPK and ERK in microglia at the L4-5 spinal cord.…”