Abstract
BackgroundActivation of extracellular signal-regulated kinase1/2 (ERK1/2) in dorsal horn of the spinal cord by peripheral inflammation is contributed to inflammatory pain hypersensitivity. Although electroacupuncture (EA) has been widely used to alleviate various kinds of pain, the underlying mechanism of EA analgesia requires further investigation. This study investigated the relationship between EA-induced analgesia and ERK signaling involved in pain hypersensitivity.MethodsThe rats were randomly divided into control, model, EA and sham EA groups. Inflammatory pain model was induced by injecting of 100 μl Complete Freund’s adjuvant (CFA) into the plantar surface of a hind paw. Rats in the EA group were treatment with EA (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1-2 mA) at 5.5 h, 24.5 h and 48.5 h. Paw withdrawal thresholds (PWTs) were measured before modeling and at 5 h, 6 h, 25 h and 49 h after CFA injection. Rats were killed and ipsilateral side of the lumbar spinal cords were harvested for detecting the expressions of p-ERK1/2, Elk1, COX-2, NK-1 and CREB by immunohistochemistry, real-time PCR, western blot analysis and EMSA. Finally, the analgesic effect of EA plus U0126, a MEK (ERK kinase) inhibitor, on CFA rats was examined.ResultsInflammatory pain was induced in rats by hindpaw injection of CFA and significantly increased phospho-ERK1/2 positive cells and protein levels of p-ERK1/2 in the ipsilateral spinal cord dorsal horn (SCDH). CFA up-regulated of cyclooxygenase-2 (COX-2) mRNA and protein expression at 6 h after injection and neurokinin-1 receptor (NK-1) expression at 49 h post-injection, in the SCDH. EA, applied to Zusanli (ST36) and Kunlun (BL60), remarkably increased the pain thresholds of CFA injected rats, significantly suppressed ERK1/2 activation and COX-2 protein expression after a single treatment, and decreased NK-1 mRNA and protein expression at 49 h. EA decreased the DNA binding activity of cAMP response element binding protein (CREB), a downstream transcription factor of ERK1/2, at 49 h after CFA injection. Moreover, EA and U0126 synergistically inhibited CFA-induced allodynia.ConclusionsThe present study suggests that EA produces analgesic effect by preventing the activation of ERK1/2-COX-2 pathway and ERK1/2-CREB-NK-1 pathway in CFA rats.
Highlights
Activation of extracellular signal-regulated kinase1/2 (ERK1/2) in dorsal horn of the spinal cord by peripheral inflammation is contributed to inflammatory pain hypersensitivity
In order to regulate gene expression, ERK1/2, as a signaling molecule, must be translocated to the nucleus to phosphorylate nuclear substrates such as Ets-like kinase 1 (Elk1) and cAMP response element binding protein (CREB) [16,17]. These findings suggest that ERK1/2 signal pathway (ERK1/2-Elk1/CREB-COX-2/neurokinin-1 receptors (NK-1)) in the dorsal horn may be a target for inflammatory pain treatment
We found that analgesic effect of transcutaneous electrical nerve stimulation (TENS) on inflammatory pain partly produced by modulating the activation of the spinal ERK1/2 [18]
Summary
Activation of extracellular signal-regulated kinase1/2 (ERK1/2) in dorsal horn of the spinal cord by peripheral inflammation is contributed to inflammatory pain hypersensitivity. The exact mechanism of inflammatory pain is still unclear, there is mounting evidence demonstrating MAPKs family play an important role in its pathphysiology [7,8,9,10], especially ERK1/2 activated in superficial dorsal horn [11]. In order to regulate gene expression, ERK1/2, as a signaling molecule, must be translocated to the nucleus to phosphorylate nuclear substrates such as Ets-like kinase 1 (Elk1) and cAMP response element binding protein (CREB) [16,17]. These findings suggest that ERK1/2 signal pathway (ERK1/2-Elk1/CREB-COX-2/NK-1) in the dorsal horn may be a target for inflammatory pain treatment
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