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

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.

• Authors: Cui-Cui Liu, Ning Lu, Yu Cui, Tao Yang, Zhi-Qi Zhao, Wen-Jun Xin, Xian-Guo Liu
• Journal: Molecular pain (Mol Pain) Vol. 6 Pg. 76 (Nov 05 2010) ISSN: 1744-8069 [Electronic] United States
• PMID: 21050491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Activating Transcription Factor 3
• Minocycline
• Paclitaxel

Topics

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