Elsevier

Neuroscience

Volume 144, Issue 2, 19 January 2007, Pages 714-720
Neuroscience

Pain mechanism
Chemotherapy-evoked painful peripheral neuropathy: Analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit

https://doi.org/10.1016/j.neuroscience.2006.09.044Get rights and content

Abstract

Chemotherapeutics in the taxane and vinca-alkaloid classes sometimes produce a painful peripheral neuropathy for which there is no validated treatment. Experiments with rat models of paclitaxel- and vincristine-evoked pain suggest that these conditions may not respond to all of the analgesics that have efficacy in other models of painful peripheral neuropathy. We tested gabapentin as a potential analgesic for paclitaxel- and vincristine-evoked pain. We used a repeated dosing paradigm because there are precedents showing that repeated drug exposure may be necessary to demonstrate analgesia in neuropathic pain models. Gabapentin is believed to work via binding to voltage-gated calcium channels that contain the alpha-2-delta type-1 (α2δ-1) subunit, and the expression of this subunit is known to be increased in some painful peripheral neuropathy models. Thus we also examined whether the paclitaxel-evoked pain syndrome was accompanied by an α2δ-1 increase, and whether gabapentin had any effect on subunit expression.

We found that the paclitaxel- and vincristine-evoked mechano-allodynia and mechano-hyperalgesia were significantly reduced by gabapentin, but only with repeated dosing. Paclitaxel-evoked painful peripheral neuropathy was associated with an increased expression of the α2δ-1 subunit in the spinal dorsal horn, but not in the dorsal root ganglia. The spinal cord increase was normalized by repeated gabapentin injections. Together, these findings suggest that repeated dosing with gabapentin may be beneficial in patients with chemotherapy-evoked painful peripheral neuropathy and that gabapentin’s mechanisms of action may include normalization of the nerve injury-evoked increase in calcium channel α2δ-1 subunit expression.

Section snippets

Experimental procedures

These experiments conformed to the ethics guidelines of the International Association for the Study of Pain (Zimmermann, 1983), the National Institutes of Health (USA), and the Canadian Institutes of Health Research. All experimental protocols were approved by the Facility Animal Care Committee of the Faculty of Medicine, McGill University in accordance with the regulations of the Canadian Council on Animal Care. Every effort was made to minimize the number of animals used and their suffering.

Vincristine time course

In the time course study (Fig. 1), vincristine-treated rats developed statistically significant increases in responding to 4 g, 8 g, and 15 g von Frey hair stimulation by day 12 (day 9 was the last day of vincristine administration). Responses returned to near normal levels by days 32–38. The clear delay between the final vincristine injection and peak symptom severity is a consistent finding in our experience and has also been noted for the paclitaxel-evoked pain syndrome (Flatters and

Analgesic efficacy

Gabapentin had significant analgesic action against the mechano-allodynia and mechano-hyperalgesia that are seen in paclitaxel- and vincristine-evoked painful peripheral neuropathies, but this action was clearly evident only after repeated dosing. A day or two of delay in the onset of analgesia would have little, if any, importance clinically. Thus, our results suggest that patients with paclitaxel- and vincristine-evoked pain may obtain relief with gabapentin. Encouraging results have been

Conclusion

Previous work has suggested that the mechanism of action for gabapentin-evoked analgesia may differ in different neuropathic pain syndromes, and that the causal role of an increase in α2δ-1 expression in producing pain hypersensitivity may also differ in different neuropathic pain conditions (Luo et al 2002, Li et al 2004, Li et al 2006). Our results are consistent with these hypotheses. Our results suggest a previously unknown effect: gabapentin-induced reversal (normalization) of the increase

Uncited references

Li CY, Song YH, Higuera ES, Luo ZD (2004).

Acknowledgments

Supported by the Mayday Fund, the Canada Foundation for Innovation, and the National Institutes of Health (G.J.B.: R01-NS052255; Z.D.L.: R01-NS40135). G.J.B. is a Canada Senior Research Chair. We thank Charles P. Taylor for preprints, Haiwei Jin for comments on the manuscript, and Chiang Siau and Lina Naso for assistance.

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