Figure 11.

Nav1.7-selective inhibitors have antinociceptive and analgesic properties in WT mice. A, B, Response latency on the 55°C hot plate test was prolonged after oral administration of GX-201 (A) or GX-585 (B), but not vehicle. C, D, Latency to withdraw the tail from a 55°C water bath was significantly longer after dosing of GX-201 (C) or GX-585 (D) compared with vehicle. E, Escape threshold in the Randall–Selitto assay was elevated in mice administered GX-585 compared with vehicle-treated controls. F, von Frey threshold was not significantly different between mice treated with GX-201 or vehicle, as expected because Nav1.7 cKO mice also do not differ from WT littermates in this assay. A, C, F, GX-201 (30 mg/kg, p.o., average total plasma concentration 10.5 ± 0.7 μm). B, D, E, GX-585 (60 mg/kg, p.o., average total plasma concentration 49.3 ± 5.4 μm). G, H, Baseline withdrawal latency from a radiant heat stimulus was recorded; then an intraplantar injection of CFA was performed. Withdrawal latencies were recorded again 24 h later (post-CFA, predose). GX-201 (30 mg/kg, p.o., average total plasma concentration 16.1 ± 1.5 μm; G) or GX-585 (60 mg/kg, p.o., average total plasma concentration 67.9 ± 15.6 μm; H) were administered, and testing was performed again 1 h later (post-CFA, postdose). Both Nav1.7 inhibitors reversed established hypersensitivity back to near pre-CFA baseline levels. I, C57BL/6 mice (n = 12/group) were administered the indicated dose of GX-585, and precapsaicin baseline von Frey thresholds were measured at the plantar footpad 1 h later. Capsaicin was injected extraterritorially at the ankle, and plantar von Frey thresholds were measured again after 30 min. GX-585 provided a dose-dependent protection from developing mechanical allodynia in this model. Average total plasma concentrations were 15.7 ± 3.1, 31.1 ± 5.3, and 60.8 ± 8.0 μm for 10, 30, and 60 mg/kg doses, respectively. J, C57BL/6 mice were dosed with vehicle (0.5% methylcellulose/0.2% Tween 80) or 60 mg/kg GX-585 1 h before testing. Vehicle-treated mice (black bars) demonstrated the expected pattern of habituation/dishabituation to the presentation of novel/familiar odor stimuli. In contrast, GX-585-treated mice were relatively indifferent to odor presentation. This may indicate perturbed olfaction after systemic administration of the drug. *p < 0.05, **p < 0.01. Statistical analysis described in Table 1. Error bars indicate SEM.