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. 2021 May 12;41(19):4349–4365. doi: 10.1523/JNEUROSCI.1940-20.2021

Figure 4.

Figure 4.

Early cKO of microglial TLR4 improves allodynia and thermal hyperalgesia in a time- and sex-specific manner without affecting acute sensitization. A, Experimental scheme for early TLR4 KO in microglia. B, Early male TLR4 cKO results in a complete and sustained reversal of existing allodynia, whereas early female TLR4 cKO significantly improves allodynia but less strikingly. n = 5-10 per group. *p < 0.05; **p < 0.01; ***p < 0.001 versus sex-matched control by two-way ANOVA with Bonferroni's post-test. C, Early male TLR4 cKO resulted in a significantly increased latency to withdrawal on a 52.5°C hot plate; however, this effect was not significant in the early females TLR4 cKO group (D). Mice were placed on an inescapable 52.5°C hot plate, and latency to first reflexive response was measured at 5 weeks after fracture. n = 5 per group. *p < 0.05 versus sex-matched control. All behavioral responses [flinching (black), guarding (gray), jumping (blue), or licking (purple)] were scored for 45 s on a 52.5°C hot plate for early male TLR4+/+ (E) and TLR4 cKO mice (F). Each row represents 1 mouse. n = 5 per group. G, Cumulative summation of flinches over 45 s for early male TLR4+/+ (dark gray) and TLR4 cKO mice (dark blue). H, Area under the curve (AUC) for summation of flinches demonstrates significant decrease in number of flinches in early male TLR4 cKO. n = 5 per group. *p < 0.05 versus sex-matched control by unpaired t test. I, Cumulative duration of nonreflexive behaviors (guarding, jumping, licking) over 45 s for TLR4+/+ (dark gray) or early TLR4 cKO (dark blue) male mice. J, AUC for duration of nonreflexive behaviors demonstrates no change with early TLR4 cKO in males. n = 5 per group. All behavioral responses were scored for 45 s on a 52.5°C hot plate for early female TLR4+/+ (K) and TLR4 cKO mice (L). Each row represents 1 mouse. n = 5 per group. M, Cumulative summation of flinches over 45 s for early female TLR4+/+ (light gray) and TLR4 cKO mice (light blue). N, AUC for summation of flinches demonstrates no significant effect of early TLR4 cKO in females. n = 5 per group. O, Cumulative duration of nonreflexive behaviors (guarding, jumping, licking) over 45 s for TLR4+/+ (light gray) or early TLR4 cKO (light blue) female mice. P, AUC for duration of nonreflexive behaviors demonstrates no change with early TLR4 cKO in females. n = 5 per group.