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. Author manuscript; available in PMC: 2024 Jul 1.
Published in final edited form as: Nat Neurosci. 2023 Jun 8;26(7):1229–1244. doi: 10.1038/s41593-023-01350-3

Fig. 6 |. Pharmacological inhibition of HDAC1/HDAC2 using RBC1HI ameliorates sensory hypersensitivity signs of opioid withdrawal.

Fig. 6 |

a, Schematic timeline of experimental design. b, RBC1HI promoted partial recovery from mechanical allodynia in groups of male mice with long-term SNI (Sham-Sal-Veh n = 7, Sham-Sal-RBC1HI n = 9; SNI-Sal-Veh n = 7, SNI-Sal-RBC1HI n = 10; repeated-measures two-way ANOVA interaction F6,58 = 5.858, P < 0.0001; Tukey’s multiple comparisons, day 20 SNI-Sal-Veh versus SNI-Sal-RBC1HI q = 5.12, d.f. = 87, P = 0.0027). c, Chronic treatment with 3 mg per kg body weight, RBC1HI prevented the development of oxycodone-induced hyperalgesia in male SNI groups exposed to chronic oxycodone. During spontaneous oxycodone withdrawal, inhibition HDAC1/HDAC2 prevented the induction of thermal hyperalgesia in both SNI and sham mice (Sham-Sal-Veh n = 7, Sham-Sal-RBC1HI n = 9; Sham-Oxy-Veh n = 8, Sham-Oxy-RBC1HI n = 10; SNI-Sal-Veh n = 7, SNI-Sal-RBC1HI n = 10; SNI-Oxy-Veh n = 8, SNI-Oxy-RBC1HI n = 7; repeated-measures two-way ANOVA interaction F28,232 = 5.01, P < 0.0001; Tukey’s multiple comparisons day 10 SNI-Oxy-Veh versus SNI-Oxy-RBC1HI q = 10.17, d.f. = 290, P < 0.0001; WD3 Sham-Oxy-Veh versus Sham-Oxy-RBC1HI q = 10.96, d.f. = 290, P < 0.0001; WD3 SNI-Oxy-Veh versus SNI-Oxy-RBC1HI q = 8.625, d.f. = 290, P < 0.0001). d,e, RBC1HI alleviated SNI-only and SNI-Oxy withdrawal-induced mechanical hypersensitivity on WD7. Five hours after Oxy administration on day 10, RBC1HI alleviated mechanical hypersensitivity in Sal-treated mice, but it did not affect the anti-allodynic response to Oxy, as Veh and RCB1H1 groups showed similar von Frey responses (SNI-Sal-Veh n = 10, SNI-Sal-RBC1HI n = 10, SNI-Oxy-Veh n = 10, SNI-Oxy-RBC1HI n = 10; repeated-measures two-way ANOVA interaction F12,144 = 4.531, P < 0.0001; Tukey’s multiple comparisons WD7 SNI-Oxy-RBC1HI versus SNI-Oxy-Veh q = 5.551, d.f. = 180, P = 0.0007; OD10 two-way ANOVA interaction F1,36 = 5.269, P = 0.0025; Sidak’s multiple comparisons SNI-Sal-Veh versus SNI-Sal-RBC1HI t = 3.112, d.f. = 36, P = 0.0072; SNI-Sal-Veh versus SNI-Oxy-Veh t = 3.589, d.f. = 36, P = 0.002). f,g, In sham mice, RCB1H1 prevented the analgesic effects of Oxy on mechanical thresholds and prevented the development of withdrawal-induced mechanical allodynia (Sham-Sal-Veh n = 9, Sham-Sal-RBC1HI n = 10, Sham-Oxy-Veh n = 9, Sham-Oxy-RBC1HI n = 10; two-way ANOVA interaction F1,34 = 5.269, P = 0.028; Sidak’s multiple comparisons OD10 Sham-Sal-Veh versus Sham-Oxy-Veh t = 2.517, d.f. = 34, P = 0.0332; OD10 Sham-Oxy-Veh versus Sham-Oxy-RBC1HI t = 2.754, d.f. = 34, P = 0.0187). h, RBC1HI pretreatment in this group of female mice also prevented the induction of thermal hyperalgesia after SNI with or without withdrawal in the Hargreaves assay (SNI-Sal-Veh n = 10, SNI-Sal-RBC1HI n = 10, SNI-Oxy-Veh n = 10, SNI-Oxy-RBC1HI n = 10; repeated-measures two-way ANOVA interaction F3,36 = 4.573, P = 0.0082; WD3 Tukey’s multiple comparisons SNI-Oxy-Veh versus SNI-Oxy-RBC1HI q = 7.742, d.f. = 72, P < 0.0001). i, When the same female Veh and RBC1HI SNI groups were tested in a 42 °C hot plate during active Oxy administration, RBC1HI ameliorated thermal hypersensitivity seen in SNI-Oxy mice (two-way ANOVA interaction F1,36 = 1.974, P = 0.1686; Sidak’s multiple comparisons OD12 SNI-Sal-Veh versus SNI-Oxy-Veh t = 2.899, d.f. = 36, P = 0.0126; OD12 SNI-Oxy-Veh versus SNI-Oxy-RBC1HI t = 2.277, d.f. = 36, P = 0.0568).j, RBC1HI effectively alleviated withdrawal-induced thermal hyperalgesia in Sham-Oxy animals (Sham-Sal-Veh n = 9, Sham-Sal-RBC1HI n = 10, Sham-Oxy-Veh n = 9, Sham-Oxy-RBC1HI n = 10; repeated-measures two-way ANOVA interaction F3,34 = 11.81, P < 0.0001; Tukey’s multiple comparisons Sham-Oxy-Veh versus Sham-Oxy-RBC1HI q = 9.016, d.f. = 68, P < 0.0001). k, There were no differences between Sham conditions in the 42 °C hot plate assay during active Oxy administration. Data indicate the mean ± s.e.m. Significance was calculated by means of two-way ANOVA with Bonferroni’s post hoc test; *P < 0.05, ***P < 0.001 and ****P < 0.0001. QD, once a day; Veh, vehicle.