Prevention of paclitaxel-induced allodynia by minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats.
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.
Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd, 2, Guangzhou, 510080, PR China.
Cui-Cui
CC
Liu
Ning
N
Lu
Yu
Y
Cui
Tao
T
Yang
Zhi-Qi
ZQ
Zhao
Wen-Jun
WJ
Xin
Xian-Guo
XG
Liu
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology*; D017239:Paclitaxel / Q000009:adverse effects*; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
D051700:Activating Transcription Factor 3; D008911:Minocycline; D017239:Paclitaxel