Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons

Int J Mol Sci. 2019 Nov 25;20(23):5917. doi: 10.3390/ijms20235917.

Abstract

Paclitaxel-induced peripheral neuropathy is a common adverse effect during paclitaxel treatment resulting in sensory abnormalities and neuropathic pain during chemotherapy and in cancer survivors. Conventional therapies are usually ineffective and possess adverse effects. Here, we examined the effects of electroacupuncture (EA) on a rat model of paclitaxel-induced neuropathic pain and related mechanisms. EA robustly and persistently alleviated paclitaxel-induced pain hypersensitivities. Mechanistically, TLR4 (Toll-Like Receptor 4) and downstream signaling MyD88 (Myeloid Differentiation Primary Response 88) and TRPV1 (Transient Receptor Potential Vallinoid 1) were upregulated in dorsal root ganglion (DRGs) of paclitaxel-treated rats, whereas EA reduced their overexpression. Ca2+ imaging further indicated that TRPV1 channel activity was enhanced in DRG neurons of paclitaxel-treated rats whereas EA suppressed the enhanced TRPV1 channel activity. Pharmacological blocking of TRPV1 mimics the analgesic effects of EA on the pain hypersensitivities, whereas capsaicin reversed EA's effect. Spinal astrocytes and microglia were activated in paclitaxel-treated rats, whereas EA reduced the activation. These results demonstrated that EA alleviates paclitaxel-induced peripheral neuropathic pain via mechanisms possibly involving suppressing TLR4 signaling and TRPV1 upregulation in DRG neurons, which further result in reduced spinal glia activation. Our work supports EA as a potential alternative therapy for paclitaxel-induced neuropathic pain.

Keywords: Paclitaxel; TLR4; TRPV1; acupuncture; dorsal root ganglion; glial cell; peripheral neuropathy.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / toxicity
  • Electroacupuncture / methods*
  • Gene Expression Regulation
  • Male
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Neuralgia / chemically induced
  • Neuralgia / metabolism
  • Neuralgia / pathology
  • Neuralgia / prevention & control*
  • Paclitaxel / toxicity*
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / pathology
  • Peripheral Nervous System Diseases / prevention & control*
  • Rats
  • Rats, Sprague-Dawley
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Myd88 protein, rat
  • Myeloid Differentiation Factor 88
  • TRPV Cation Channels
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Trpv1 protein, rat
  • Paclitaxel