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. 2021 Jul 28;163(4):753–764. doi: 10.1097/j.pain.0000000000002421

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Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Figure 6. — DS-437 reduced DRG neuronal excitability and relieved pain hypersensitivity in Scn11a ^A796G/A796G mice. (A) Current-clamp responses to a 200-ms depolarizing current of 200 pA in representative Scn11a ^+/+ mouse DRG neurons and Scn11a ^A796G/A796G mouse DRG neurons with DS-437 or control. (B) Rheobase, (C) resting membrane potential (RMP), and (D) V_threshold (the threshold at which AP takeoff occurs) showed no significant changes in DRG neurons treated with or without DS-437. Data were statistically analysed by one-way ANOVA; *P < 0.05 compared with the control. (E) Comparison of the average spike numbers of repetitive action potentials (APs) fired in response to the 200-ms current injection ranging from 0 to 225 pA in DRG neurons (Na_V1.9-WT + control, n = 21; Na_V1.9-WT + 100 μM DS-437, n = 22; Na_V1.9-KI + control, n = 30; Na_V1.9-KI + 10 μM DS-437, n = 22; Na_V1.9-KI + 100 μM DS-437, n = 24). Significant differences were tested by two-way ANOVA, followed by a post hoc Bonferroni test; DS-437 × current: F(36, 1041) = 2.049, P = 0.0003; DS-437: F(3, 1041) = 50.86, P < 0.0001; current: F(9, 1041) = 74.58, P < 0.0001; **P < 0.01 and ***P < 0.001 compared with the control. (F) The duration of licking and lifting behaviours in Na_V1.9-KI mice and Na_V1.9-WT in the 45 minutes after intraplantar administration of formalin to the hind paws binned at 5-min intervals. (G) Data from 2 phases of the formalin test are summarized. Phase I: 0 to 10 minutes. Phase II: 10 to 45 minutes (saline, n = 6; DS-437, n = 6). Significant differences were tested by one-way ANOVA; *P < 0.05 and **P < 0.01 compared with saline. (H) Heat threshold was assessed using the hot-plate test. (I) Mechanical withdrawal threshold was tested by applying von Frey filaments (saline, n = 6; DS-437, n = 6). Significant differences were tested by two-way ANOVA; *P < 0.05, **P < 0.01, and ***P < 0.001 compared with saline. ANOVA, analysis of variance; DRG, dorsal root ganglion.