Role of protein kinase Cϵ and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat
Section snippets
Animals
Experiments were performed on 280–300 g male Sprague–Dawley rats (Bantin and Kingman, Fremont, CA, USA). Rats were housed in a temperature- and humidity-controlled environment and maintained in a 12-h light–dark cycle. Food and water were available ad libitum. The experimental protocol was approved by the Committee on Animal Research at the University of California at San Francisco and adhered to the National Institutes of Health Guidelines for the use of Animals in Research. All efforts were
Weight
Immediately prior to initiation of treatment (i.e. day 0), animals assigned to receive Taxol (n=10) weighed 214.4±39.9 g compared with 223.9±41.1 g in animals assigned to receive Cremophore vehicle (n=7). After 12 days, the weight of rats that received Taxol (270.0±42.9 g) was not significantly different (P>0.05) from that of vehicle-treated rats (254.9±21.3 g).
Mechanical nociceptive threshold (mechanical hyperalgesia)
Before the administration of Taxol (1 mg/kg), the mean paw-withdrawal threshold of the Taxol group (115.8±2.4 g, n=8, Fig. 1A) was not
Discussion
The use of the antineoplastic drug paclitaxel (Taxol) for the treatment of a variety of cancers is significantly limited by the development of a dose-related painful peripheral neuropathy, thought to be caused by its ability to disrupt microtubule function (Lipton et al., 1989, Rowinsky et al., 1993c, Cavaletti et al., 1995b, Cavaletti et al., 2000). We report the development of a rat model of Taxol-induced painful peripheral neuropathy and describe the contribution of two second messengers,
Conclusion
We have shown that both acute and chronic hyperalgesia can be demonstrated in a model of Taxol-induced peripheral neuropathy in the rat. We have also established that both PKCϵ and PKA second messenger pathways contribute to Taxol hyperalgesia. These findings provide insight into the mechanism of Taxol-induced painful peripheral neuropathy that may help control side effects of chemotherapy and improve its clinical efficacy.
Acknowledgements
This work was funded by NIH (DE08973).
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