<p>Electroacupuncture Treatment Attenuates Paclitaxel-Induced Neuropathic Pain in Rats via Inhibiting Spinal Glia and the TLR4/NF-κB Pathway</p>

Abstract

Background and Purpose: Neuropathic pain is a major side-effect of paclitaxel (PTX) chemotherapy. Although the precise mechanisms responsible for this pain are unclear, the activation of neuroglia and upregulation of the TLR4/NF-κB pathway are known to be involved. In this study, we determined whether electroacupuncture (EA) could limit mechanical hypersensitivity resulting from the chemotherapeutic drug PTX in rats, and investigated the potential mechanisms involved. Methods: Rats intraperitoneally received a cumulative dose of 8 mg/kg PTX (2 mg/kg per day) or vehicle control on alternate days (day 0, 2, 4 and 6). EA treatment (10 Hz, 1 mA) was applied at bilateral ST36 acupoints in rats once every other day on days 0-14. For sham EA, needles were inserted at ST36 acupoints without electrical stimulation. Mechanical allodynia was measured by mechanical withdrawal latency (MWL) of paws to a mechanical stimulus every 2 days. Protein expression of TLR4 and NF-κB p65, as well as TMEM119 and GFAP (indicators of microglia and astrocytes, respectively) in spinal cord was quantified by Western blot analysis. Levels of inflammatory cytokines IL-1β and TNF-α in spinal cord and serum were detected by ELISA. Results: Mechanical allodynia induced by PTX in both paws (right and left) of rats was significantly attenuated by EA but not sham EA treatment. In addition, EA, but not sham EA, inhibited the activation of both microglia (TMEM119) and astrocytes (GFAP) in lumbar spinal cord. Moreover, Western blot analysis revealed that protein expression of TLR4 and NF-κB in spinal cord was suppressed by EA but not sham EA treatment. PTX significantly increased inflammatory cytokines in spinal cord and serum, which were ameliorated by EA treatment but not by sham EA. Conclusion: These results indicate that EA treatment attenuates PTX-induced mechanical allodynia. The putative mechanism corroborating this finding could be related to the suppression of activated microglia and astrocytes in spinal cord, as well as the inhibition of the activated TLR4/NF-κB signaling pathway by EA treatment.

Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain

“…However, an earlier study by Zheng et al report no increment of spinal microglia activation associated with paclitaxel neuropathy using the same rat model as we used. In contrast, some recent studies reported obvious spinal microglia activation using the same paclitaxel model as we used in the present study [ 49 ]. Moreover, our recent study, which used the same paclitaxel model, also identified significant spinal microglia activation after paclitaxel treatment and we further evaluated the effect of electroacupuncture on alleviating microglia activation in spinal cord [ 11 ].…”

“…ERK1/2 signaling was recently found to be upregulated and contributed to PIPN by enhancing Nav1.7 expression in DRGs of a rat model of PIPN [ 74 ]. Besides, NF-κB signaling was shown to be upregulated in the spinal cord of a rat PIPN model [ 75 ]. These results suggest that lncRNAs may modulate mRNA expression involved in neurotrophin signaling pathway during PIPN, which may consequently affect downstream ERK1/2 s and NF-κB signaling.…”

Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA‐101 expression and the E2F2–TLR4–NF‐κB axis

“…Similarly, an inhibitor of TLR4–NF‐κB signalling, pyrollidine dithiocarbamate, mitigated the spared nerve injury‐induced production of proinflammatory cytokines (Pei et al., 2018). Meanwhile, electroacupuncture attenuated paclitaxel‐induced mechanical allodynia, which was related to the inhibition of microglia and astrocytes in spinal cord, as well as the blockage of the TLR4–NF‐κB signalling pathway (Zhao et al., 2020). In the present study, TLR4–NF‐κB signalling activation by LPS significantly restored the mechanical allodynia, thermal hyperalgesia, apoptosis and the production of inflammation‐related factors reduced by Dex.…”

The Role of Neuroglial Crosstalk and Synaptic Plasticity-Mediated Central Sensitization in Acupuncture Analgesia

“…Paclitaxel significantly activates both microglia and astrocytes and increases the expression of inflammatory cytokines (IL-1 β and TNF- α ) in the lumbar spinal cord. EA treatment (10 Hz, 1 mA) at the bilateral ST36 point in rats suppressed the expression of inflammatory cytokines through the downregulation of the TLR4/NF- κ B pathway as well as suppressing activated microglia and astrocytes [ 71 ]. Besides TLR4, increased expression of TLR2 in the spinal cord and thalamus was also reportedly suppressed by EA in a CFA model [ 72 ].…”