Enantioselective relief of neuropathic pain by systemic mexiletine in the rat

The many pharmacologically diverse molecules that are able to reduce neuropathic pain might do so through a common action on neuronal Na+ channels. Here we compare the potency for relieving allodynia from rat nerve root (L5-L6) ligation by mexiletine enantiomers known to stereoselectively inhibit Na+ channels. After programmed intravenous infusions of R(-)- and S(+)-mexiletine to plasma concentrations of 0.5 to 2.0 mu g/mL for 25 minutes 5 to 10 days after unilateral nerve root ligation of male Sprague-Dawley rats (Taconic Farms, Germantown. NY), allodynia was tested by the von Frey filament force necessary for hindpaw withdrawal. Allodynia in operated rats (paw withdrawal threshold [PWT] = 1 to 2 g versus 11 to 12 g in unoperated controls) was unrelieved by S(+)-mexiletine from 0.5 to 1.4 mu g/mL; convulsive-like behavior appeared at 2.0 mu g/mL S(+)- and R(-)mexiletine. R(-)-mexiletine at 0.5 mu g/mL was ineffective, but 1.0, 1.2, and 1.4 mu g/mL all raised PWT values to 7 to 8 g, corresponding to 60% recovery Racemic mexiletine was ineffective at 1.0 mu g/mL but equieffective to R(-)-mexiletine at 1.2 and 1.4 mu g/mL. The findings of enantioselective pain relief are consistent with the published reports of R(-)-mexiletine's greater potency for inhibition of Na+ channels.