Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy

Pain. 2017 Mar;158(3):417-429. doi: 10.1097/j.pain.0000000000000774.


Here, it is shown that paclitaxel-induced neuropathy is associated with the development of spontaneous activity (SA) and hyperexcitability in dorsal root ganglion (DRG) neurons that is paralleled by increased expression of low-voltage-activated calcium channels (T-type; Cav3.2). The percentage of DRG neurons showing SA and the overall mean rate of SA were significantly higher at day 7 in rats receiving paclitaxel treatment than in rats receiving vehicle. Cav3.2 expression was increased in L4-L6 DRG and spinal cord segments in paclitaxel-treated rats, localized to small calcitonin gene-related peptide and isolectin B4 expressing DRG neurons and to glial fibrillary acidic protein-positive spinal cord cells. Cav3.2 expression was also co-localized with toll-like receptor 4 (TLR4) in both the DRG and the dorsal horn. T-type current amplitudes and density were increased at day 7 after paclitaxel treatment. Perfusion of the TLR4 agonist lipopolysaccharide directly activated DRG neurons, whereas this was prevented by pretreatment with the specific T-type calcium channel inhibitor ML218 hydrochloride. Paclitaxel-induced behavioral hypersensitivity to mechanical stimuli in rats was prevented but not reversed by spinal administration of ML218 hydrochloride or intravenous injection of the TLR4 antagonist TAK242. Paclitaxel induced inward current and action potential discharges in cultured human DRG neurons, and this was blocked by ML218 hydrochloride pretreatment. Furthermore, ML218 hydrochloride decreased firing frequency in human DRG, where spontaneous action potentials were present. In summary, Cav3.2 in concert with TLR4 in DRG neurons appears to contribute to paclitaxel-induced neuropathy.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Azabicyclo Compounds / therapeutic use
  • Benzamides / therapeutic use
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcium Channel Blockers / therapeutic use
  • Calcium Channels, T-Type / metabolism*
  • Disease Models, Animal
  • Ganglia, Spinal / pathology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Hyperalgesia / etiology*
  • Male
  • Paclitaxel* / adverse effects
  • Paclitaxel* / pharmacology
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / complications*
  • Peripheral Nervous System Diseases / pathology*
  • Peripheral Nervous System Diseases / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Sulfonamides / therapeutic use
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / metabolism


  • Antineoplastic Agents, Phytogenic
  • Azabicyclo Compounds
  • Benzamides
  • Cacna1h protein, rat
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • ML218 compound
  • Sulfonamides
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • Calcitonin Gene-Related Peptide
  • Paclitaxel