Figure 2.

Effect of repeated dosing Pregabalin or single dosing Mexiletine, Pregabalin, and CC4148 on neuropathic pain measures and coordination test in STZ-induced diabetic rats. Neuropathic pain was assessed every 1–2 weeks with the von Frey test for tactile allodynia pain (a) and the plantar test for thermal hyperalgesia pain (b) in STZ-injected or sham-injected animals. Neuropathic pain fully developed over 5 weeks after a STZ injection and lasted through the end of the study, more than one year. Chronic administration of Pregabalin in the animals' drinking water for 8 weeks inhibited pain (a–b). However, Pregabalin showed side effects at 30 mg/kg/day, so the dose was reduced to 15 mg/kg/day on day 2 of week 12. After 3–4 weeks of dosing, the efficacy of Pregabalin started to attenuate, so the dose was increased to 20 mg/kg/day for the final two weeks of dosing. A single dose of Pregabalin 30 mg/kg by oral gavage also caused side effects of sleepiness and a decrease in coordination as measured by the foot fault test (d). An acute administration of Mexiletine at 30 and 40 mg/kg by oral gavage significantly and dose-responsively inhibited thermal hyperalgesia via the plantar test (c) with side effects showed in the foot fault test (d). A selective Nav1.7 blocker, CC4148, at 30 mg/kg by an intraperitoneal injection (i.p.) showed significant inhibition on thermal hyperalgesia pain (c) and no evidence of central nerve system and muscular adverse effects via the foot fault test (d). Behavior tests were conducted 30′ after oral gavage or i.p. and between 9 and 10 AM in the chronic study. N = 10–12, mean ± s.e. were calculated from each group at each time point, two-tailed (α = 2), Student's t-test, ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001 (compared to vehicle), #p < 0.05 (compared to sham).