The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats

Abstract

Chemotherapy-induced pain is the most common treatment-limiting complication encountered by cancer patients receiving taxane-, vinca alkaloid- or platin-based chemotherapy. Several lines of evidence indicate that activation of pro-inflammatory cascades involving the release of cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) as well as various growth factors are key events in the pathogenesis of many types of nerve-injury related pain. Similar mechanisms might also be involved in the etiology of chemotherapy-induced pain. Thalidomide and minocycline have profound immunomodulatory actions in addition to their originally intended pharmacological actions. These compounds were evaluated here for effects in preventing the development of taxol-induced mechanical and thermal hyperalgesia in rats. Thalidomide (50.0 mg/kg) reduced taxol-induced mechanical allodynia and hyperalgesia whereas minocycline (20.0 mg/kg) reduced taxol-induced mechanical hyperalgesia and allodynia as well as taxol-induced thermal hyperalgesia. These results suggest that immunomodulatory agents may provide a treatment option for the protection or reversal of chemotherapy-related pain.

Figure 1

Taxol produces mechanical hyperalgesia that is blocked by thalidomide. The scatter and line plots show the time course of change in the 50% mechanical withdrawal threshold to the application of vonFrey filaments to the mid-plantar surface of the hindpaws (vehicle, open circles; taxol alone, filled circles; filled squares, taxol-thalidomide; open squares, thalidomide alone); whereas the bar graphs (bottom of figure) show the mean percentage of withdrawal responses shown by each treatment group (vehicle, open bars; taxol alone, grey bars; taxol-thalidomide, cross-hatched bars; thalidomide alone, black bars) to the lowest force vonFrey filament that was tested (1.14g). Taxol produced a significant decrease in 50% withdrawal threshold by day 7 of the experiment when compared to vehicle treatment. This was due to a significantly increased withdrawal frequency to both low and high strength filaments. Thalidomide attenuated taxol-induced hyperalgesia such that the 50% withdrawal threshold was not different from vehicle. Thalidomide alone had no effect on mechanical withdrawal threshold. Stars indicate statistical difference from vehicle whereas the diamonds indicate statistical difference from taxol. One symbol, p<0.05; two symbols, p<0.01; three symbols, p<0.001.

Figure 2

Taxol produces mechanical hyperalgesia that is blocked by minocycline. The scatter and line plots (top of figure) show the time course of change in the 50% mechanical withdrawal threshold to the application of vonFrey filaments to the mid-plantar surface of the hindpaws (vehicle, open circles; taxol alone, filled circles; taxol-minocycline, filled triangles, minocycline alone, open triangles); whereas the bar graphs (bottom of figure) show the mean percentage of withdrawal responses shown by each treatment group (vehicle, open bars; taxol, grey bars; taxol-minocycline, checkered bars; minocycline alone, black bars) to the lowest vonFrey filaments (1.14g) tested. Minocycline prevented taxol-induced hyperalgesia such that the 50% withdrawal threshold was never different from vehicle until well after the drug was discontinued. As shown in the bar graphs, the effects of minocycline were evident in preventing taxol-induced changes in the responses of both low and high strength von Frey filaments. Minocycline alone had no effect on mechanical withdrawal. Stars indicate statistical difference from vehicle whereas the diamonds indicate statistical difference from taxol. One symbol, p<0.05; two symbols, p<0.01; three symbols, p<0.001.

Figure 3

Minocycline prevents taxol-induced thermal hyperalgesia but thalidomide does not. The scatter and line graphs show the mean difference in mean paw withdrawal latency for the vehicle (open circles), taxol-vehicle (filled circles), thalidomide-taxol (filled squares, upper panel), and minocycline-taxol (filled triangles, lower panel) rats for each day of the experiment in comparison to the baseline mean paw withdrawal latency. Taxol produced thermal hyperalgesia that was significant from day 7 of the experiment. Similarly, the thalidomide-taxol treated rats also showed thermal hyperalgesia that was significant from day 7 of the experiment (upper panel). In contrast, minocycline-taxol treated rats did not develop any change in mean paw withdrawal latency that was significantly different from baseline at any time point in the study. Stars indicate points of significant difference between vehicle and vehicle, diamonds indicate points of significant difference between thalidomide-taxol and vehicle, and crosses indicate points of significant difference between minocycline-taxol and taxol.

Figure 4

The scatter and line plots show the mean duration that animals in each treatment group remained on the rotarod over the time course of the experiment. Rats in the vehicle-taxol group showed a lower mean rotarod time at days 1 and 3 of the experiment but these differences were not statistically different from the vehicle group times. The rotarod times for all groups became essentially identical by day 5 and remained so for the remainder of the experiment. Open circles, vehicle; filled circles, taxol; filled squares, thalidomide-taxol; filled triangles, minocycline-taxol.