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

Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ, Liu XG - Mol Pain (2010)

Bottom Line: Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3.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 finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd, 2, Guangzhou, 510080, PR China.

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.

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Minocycline blocked the paclitaxel-induced mechanical allodynia. Application of paclitaxel (cumulative dose 24 mg/kg; 3 × 8 mg/kg) induced a marked and prolonged mechanical allodynia. On day 4, 8 and 12 after first paclitaxel treatment, the paclitaxel rats showed a significant decrease in 50% withdrawal threshold relative to the vehicle group. *P < 0.05; **P < 0.01. Minocycline pretreatment at dose of 30 mg/kg or 50 mg/kg significantly attenuated paclitaxel-induced mechanical allodynia compared with the corresponding time points of paclitaxel group, respectively. # P < 0.05; ##P < 0.01 and † P < 0.05; †† P < 0.01. However, 50% withdrawal threshold had no significant difference between the 30 mg/kg minocycline/paclitaxel group and the 50 mg/kg minocycline/paclitaxel group or the vehicle group. Minocycline at 30 mg/kg alone had no effect on the mechanical withdrawal threshold in control animals (n = 8/group).
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Figure 1: Minocycline blocked the paclitaxel-induced mechanical allodynia. Application of paclitaxel (cumulative dose 24 mg/kg; 3 × 8 mg/kg) induced a marked and prolonged mechanical allodynia. On day 4, 8 and 12 after first paclitaxel treatment, the paclitaxel rats showed a significant decrease in 50% withdrawal threshold relative to the vehicle group. *P < 0.05; **P < 0.01. Minocycline pretreatment at dose of 30 mg/kg or 50 mg/kg significantly attenuated paclitaxel-induced mechanical allodynia compared with the corresponding time points of paclitaxel group, respectively. # P < 0.05; ##P < 0.01 and † P < 0.05; †† P < 0.01. However, 50% withdrawal threshold had no significant difference between the 30 mg/kg minocycline/paclitaxel group and the 50 mg/kg minocycline/paclitaxel group or the vehicle group. Minocycline at 30 mg/kg alone had no effect on the mechanical withdrawal threshold in control animals (n = 8/group).

Mentions: The administration of paclitaxel at a cumulative dose of 24 mg/kg (3 × 8 mg/kg, 3 days apart, i.p) caused a marked and prolonged mechanical allodynia as evidenced by 50% withdrawal threshold compared with day 0 (P < 0.05). On day 4 and 12 following initial paclitaxel treatment, the 50% withdrawal threshold significantly reduced to 8.87 ± 1.33 g and 3.03 ± 1.92 g respectively compared with the value (17.28 ± 1.85 g) on day 0 (Figure 1). Application of minocycline at a daily dosage of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, initiated one day before paclitaxel and continued for 8 days significantly attenuated mechanical allodynia on day 4, 8 (P < 0.05) and 12 (P < 0.01) compared with the paclitaxel group. Furthermore, 50% withdrawal threshold had no significantly difference between the 30 mg/kg minocycline/paclitaxel group and the 50 mg/kg minocycline/paclitaxel group or the vehicle group. Continuous injection of minocycline at a dose of 30 mg/kg alone had no effect on mechanical hypersensivity in rats (Figure 1), so the dose of 30 mg/kg of minocycline was applied in subsequent experiments.


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

Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ, Liu XG - Mol Pain (2010)

Minocycline blocked the paclitaxel-induced mechanical allodynia. Application of paclitaxel (cumulative dose 24 mg/kg; 3 × 8 mg/kg) induced a marked and prolonged mechanical allodynia. On day 4, 8 and 12 after first paclitaxel treatment, the paclitaxel rats showed a significant decrease in 50% withdrawal threshold relative to the vehicle group. *P < 0.05; **P < 0.01. Minocycline pretreatment at dose of 30 mg/kg or 50 mg/kg significantly attenuated paclitaxel-induced mechanical allodynia compared with the corresponding time points of paclitaxel group, respectively. # P < 0.05; ##P < 0.01 and † P < 0.05; †† P < 0.01. However, 50% withdrawal threshold had no significant difference between the 30 mg/kg minocycline/paclitaxel group and the 50 mg/kg minocycline/paclitaxel group or the vehicle group. Minocycline at 30 mg/kg alone had no effect on the mechanical withdrawal threshold in control animals (n = 8/group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991291&req=5

Figure 1: Minocycline blocked the paclitaxel-induced mechanical allodynia. Application of paclitaxel (cumulative dose 24 mg/kg; 3 × 8 mg/kg) induced a marked and prolonged mechanical allodynia. On day 4, 8 and 12 after first paclitaxel treatment, the paclitaxel rats showed a significant decrease in 50% withdrawal threshold relative to the vehicle group. *P < 0.05; **P < 0.01. Minocycline pretreatment at dose of 30 mg/kg or 50 mg/kg significantly attenuated paclitaxel-induced mechanical allodynia compared with the corresponding time points of paclitaxel group, respectively. # P < 0.05; ##P < 0.01 and † P < 0.05; †† P < 0.01. However, 50% withdrawal threshold had no significant difference between the 30 mg/kg minocycline/paclitaxel group and the 50 mg/kg minocycline/paclitaxel group or the vehicle group. Minocycline at 30 mg/kg alone had no effect on the mechanical withdrawal threshold in control animals (n = 8/group).
Mentions: The administration of paclitaxel at a cumulative dose of 24 mg/kg (3 × 8 mg/kg, 3 days apart, i.p) caused a marked and prolonged mechanical allodynia as evidenced by 50% withdrawal threshold compared with day 0 (P < 0.05). On day 4 and 12 following initial paclitaxel treatment, the 50% withdrawal threshold significantly reduced to 8.87 ± 1.33 g and 3.03 ± 1.92 g respectively compared with the value (17.28 ± 1.85 g) on day 0 (Figure 1). Application of minocycline at a daily dosage of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, initiated one day before paclitaxel and continued for 8 days significantly attenuated mechanical allodynia on day 4, 8 (P < 0.05) and 12 (P < 0.01) compared with the paclitaxel group. Furthermore, 50% withdrawal threshold had no significantly difference between the 30 mg/kg minocycline/paclitaxel group and the 50 mg/kg minocycline/paclitaxel group or the vehicle group. Continuous injection of minocycline at a dose of 30 mg/kg alone had no effect on mechanical hypersensivity in rats (Figure 1), so the dose of 30 mg/kg of minocycline was applied in subsequent experiments.

Bottom Line: Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3.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 finding might provide potential target for preventing paclitaxel-induced neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd, 2, Guangzhou, 510080, PR China.

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.

Show MeSH
Related in: MedlinePlus