Elsevier

Neuroscience

Volume 108, Issue 3, 14 December 2001, Pages 507-515
Neuroscience

Role of protein kinase Cϵ and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat

https://doi.org/10.1016/S0306-4522(01)00425-0Get rights and content

Abstract

The clinical use of the antineoplastic agent paclitaxel (Taxol) is significantly limited in its effectiveness by a dose-related painful peripheral neuropathy. To evaluate underlying mechanisms, we developed a model of Taxol-induced painful peripheral neuropathy in the rat and determined the involvement of two second messengers that contribute to enhanced nociception in other models of inflammatory and neuropathic pain, protein kinase Cϵ and protein kinase A. Taxol administered acutely, or chronically over 12 days, produced a decrease in mechanical nociceptive threshold. Acutely, Taxol induced hyperalgesia that was significant within 1 h, maximal after 6 h and resolved completely by 24 h after a single treatment. Chronically, Taxol treatment resulted in a dose (0.1–1 mg/kg/day)-dependent decrease in nociceptive threshold, measured 24 h after administration, maximal within 5 days from the commencement of Taxol administration and resolving by 2 weeks after the last dose of Taxol. Chronic Taxol treatment also increased the number of action potentials evoked by sustained (60-s) threshold and suprathreshold (10-g) stimulation of a sub-population of C-fibers in rats with Taxol-induced hyperalgesia. Mechanical allodynia and thermal hyperalgesia were also present in Taxol-treated rats. Hyperalgesia, produced by both acute and chronic Taxol, was attenuated by intradermal injection of selective second messenger antagonists for protein kinase Cϵ and protein kinase A.

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.

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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