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[Preprint]. 2024 Aug 8:2024.08.07.606891. [Version 1] doi: 10.1101/2024.08.07.606891

Figure 4:

Figure 4:

GPR88 causes mechanical hypersensitivity in primed animals after IL-6 treatment. A) Expression of Grp88 mRNA is higher in paclitaxel-treated animals after the resolution of paclitaxel-induced pain behaviors. B) Schematic representation of dosing paradigm for intraplantar injection of IL-6, PGE2, or RTI-13951–33 (GPR88 agonist) and von Frey assessment. C) 100 ng and 1 μg RTI-13951–33 induce mechanical hypersensitivity only in primed mice that were previously treated with IL-6 (Two-way ANOVA, F= 5.173, p <0.0001, Tukey’s multiple comparison test, (Vehicle+PGE2, N=5, IL-6+1 μg RTI-13951–33, N=6, IL-6+100 ng RTI-13951–33, N=6, Vehicle+1 μg RTI-13951–33, N=5), Day 1 post PGE2 or RTI-13951–33, IL-6+PGE2 vs. Veh+1 μg RTI-13951–33, p-value = 0.0205, IL-6+1 μg RTI-13951–33 vs. Veh+1 μg RTI-13951–33, p-value = 0.0311, IL-6+100 ng RTI-13951–33 vs. Veh+1 μg RTI-13951–33, p-value = 0.0471, Day 2 post PGE2 or RTI-13951–33 administration IL-6+PGE2 vs. Veh+1 μg RTI-13951–33, p-value = < 0.0001, IL-6+1 μg RTI-13951–33 vs. Veh+1 μg RTI-13951–33, p-value = 0.0005, IL-6+100 ng RTI-13951–33 vs. Veh+1 μg RTI-13951–33, p-value = 0.0003, Veh+PGE2 vs. IL-6+PGE2, p-value = 0.0153, Veh+PGE2 vs. IL-6+1 μg RTI-13951–33, p-value = 0.0403, Veh+PGE2 vs. IL-6+100 ng RTI-13951–33, p-value = 0.0287. Data represents mean ± SEM. Significance represented as IL-6+1 μg RTI-13951–33 vs. Veh+1 μg RTI-13951–33 (pink*), IL-6+100 ng RTI-13951–33 vs. Veh+1 μg RTI-13951–33 (blue*), Veh+RTI-13951–33 vs. IL-6+PGE2 (yellow*). D) Effect size was determined by calculating the sum of the cumulative difference between the value for each time point post-GPR88 agonist administration and the day 12 baseline value. We observed a significant difference for both 100 ng and 1 μg RTI-13951–33 treatment between the Vehicle group and IL-6 primed animals. (Two-way ANOVA, p-value = <0.0001, Tukey’s multiple comparison test, 100 ng RTI-13951–33:IL-6 vs. 1 μg RTI-13951–33: Vehicle, p-value = 0.0002, 100 ng RTI-13951–33:IL-6 vs. PGE2:Vehicle, p-value = 0.0003, 1 μg RTI-13951–33:Vehicle vs. 1 μg RTI-13951–33:IL-6, p-value = <0.0001, 1 μg RTI-13951–33:Vehicle vs. PGE2:IL-6, p-value = 0.0002, 1 μg RTI-13951–33:IL-6 vs. PGE2:Vehicle, p-value = 0.0002, PGE2:Vehicle vs. PGE2:IL-6, p-value = <0.0001. E) Grimacing behavior was observed to be significantly different in animals treated with RTI-13951–33 compared to its baseline measurement. (Two-way ANOVA, F=4.834, p-value = 0.0003, Dunnett’s multiple comparison test, Day1 IL-6+PGE2 vs Baseline, p-value = 0.0261, IL-6+1 μg RTI-13951–33 vs Baseline, p-value = 0.0051, IL-6+100 ng RTI-13951–33 vs Baseline, p-value = 0.0022, Day2, IL-6+PGE2 vs Baseline, p-value = 0.0358, IL-6+1 μg RTI-13951–33 vs Baseline, p-value = 0.0024, IL-6+ 100 ng RTI-13951–33 vs Baseline, p-value = 0.0282). Data represents mean +/− SEM.