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

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 (alpha(2)delta-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 alpha(2)delta-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 alpha(2)delta-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 alpha(2)delta-1 subunit expression.

Fig. 1

Time course of mechano-allodynia (responses to 4 g von Frey hair) and mechano-hyperalgesia (responses to 8 g and 15 g von Frey hairs) produced by 10 consecutive daily doses (starting on D0, ending on D9) of vincristine (50 μg/kg, i.p.). * P<0.05; ^# P<0.01; ^‡ P<0.001. Vehicle group: n=6–13/time point; vincristine group: n=11–23/time point.

Fig. 2

Responses to four consecutive daily injections of gabapentin (100 mg/kg, i.p.) in rats with vincristine-evoked neuropathic pain. Naïve BL: response level prior to receiving vincristine; Vinc. BL: post-vincristine baseline response level on D17 after the first injection of vincristine (one day before the start of gabapentin dosing). * P<0.05; ^# P<0.01; ^‡ P<0.001.

Fig. 3

. Responses to four consecutive daily injections of gabapentin (100 mg/kg, i.p.) in rats with paclitaxel-evoked neuropathic pain. Naïve BL: response level prior to receiving paclitaxel; Pacli. BL: post-paclitaxel baseline response level on D26 after the first injection of paclitaxel (one day before the start of gabapentin dosing). * P<0.05; ^# P<0.01; ^‡ P<0.001.

Fig. 4

α₂δ-1 Subunit protein levels in DRG (A) and dorsal spinal cord (B) of paclitaxel-treated animals after saline or gabapentin treatment (n=7/group). Samples in the representative Western blot in each panel are arranged in the same order as that indicated in the bar graph summaries. GAPDH bands were used as internal controls for protein loading. * P<0.05 compared with the third injection of saline group. ^# P<0.05 compared with the first injection of gabapentin group. ⁺ P<0.05 compared with naïve group.