Prevention of paclitaxel-induced allodynia by minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats

Mol Pain. 2010 Nov 5;6:76. doi: 10.1186/1744-8069-6-76.

Abstract

Background: Although paclitaxel is a frontline antineoplastic agent for treatment of solid tumors, the paclitaxel-evoked pain syndrome is a serious problem for patients. There is currently no valid drug to prevent or treat the paclitaxel-induced allodynia, partly due to lack of understanding regarding the cellular mechanism. Studies have shown that minocycline, an inhibitor of microglia/macrophage, prevented neuropathic pain and promoted neuronal survival in animal models of neurodegenerative disease. Recently, Cata et al also reported that minocycline inhibited allodynia induced by low-dose paclitaxel (2 mg/kg) in rats, but the mechanism is still unclear.

Results: Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF) in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3) in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg) in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats.

Conclusions: Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Cell Movement / drug effects*
  • Fluorescent Antibody Technique
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / pathology
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / pathology
  • Hyperalgesia / prevention & control*
  • Macrophages / drug effects
  • Macrophages / pathology*
  • Male
  • Minocycline / pharmacology*
  • Nerve Fibers / drug effects
  • Nerve Fibers / pathology*
  • Paclitaxel / adverse effects*
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / pathology
  • Protein Transport / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / drug effects

Substances

  • Activating Transcription Factor 3
  • Minocycline
  • Paclitaxel