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. 2022 Feb 16;42(7):1196–1210. doi: 10.1523/JNEUROSCI.1982-21.2021

Figure 3.

Figure 3.

Role of Gαi3 in hyperalgesia and hyperalgesic priming produced by systemic sub-AD fentanyl and morphine. Rats received injection of AS-ODN (120 μg in 20 μl/d, i.t.) or SE-ODN (120 μg in 20 μl/d, i.t.) against Gαi3 mRNA, daily for 3 consecutive days. A, B, On the fourth day, ∼17 h after the third intrathecal administration of ODNs, at which time mechanical nociceptive threshold was not significantly different from pre-ODN baselines (A: SE-ODN-treated group: t(5) = 0.67, p = 0.53; AS-ODN-treated group: t(5) = 0.18, p = 0.86; B: SE-ODN-treated group: t(5) = 0.39, p = 0.71; AS-ODN-treated group: t(5) = 0.15, p = 0.89, when the mechanical nociceptive threshold is compared before and after the third Gαi3 ODN injection; paired Student's t test), sub-AD fentanyl (A: 0.01 mg/kg, s.c.) or morphine (B: 0.03 mg/kg, s.c.) was administered and the mechanical nociceptive threshold was evaluated 1 h later. In the Gαi3 AS-ODN-treated group, systemic sub-AD of neither fentanyl (A) nor morphine (B) produced hyperalgesia, measured 1 h after its administration, as is observed in the Gαi3 SE-ODN-treated group (A: F(1,10) = 186.6, ****p < 0.0001; B: F(1,10) = 193.9, ****p < 0.0001, when the hyperalgesia in the Gαi3 SE-ODN-treated and the AS-ODN-treated groups was compared at 1 h after systemic sub-AD opioids; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). At the end of the fourth day, rats again received intrathecal Gαi3 AS-ODN or SE-ODN. C, D, Five days after systemic sub-AD fentanyl and morphine, at which time mechanical nociceptive threshold was not different from preopioid baselines (C: SE-ODN-treated group: t(5) = 1.98, p = 0.11; AS-ODN-treated group that received sub-AD fentanyl: t(5) = 1.07, p = 0.33; D: SE-ODN-treated group: t(5) = 0.22; p = 0.83; AS-ODN-treated group that received sub-AD morphine: t(5) = 2.23, p = 0.07, when the mechanical nociceptive threshold is compared before and 5 d after systemic sub-AD opioid; paired Student's t test), PGE2 (100 ng/5 μl, i.d.) was injected and mechanical nociceptive threshold was evaluated 30 min and 4 h later. In the Gαi3 AS-ODN-treated group, which received systemic sub-AD fentanyl, PGE2-induced hyperalgesia was not present at the fourth hour (C: F(1,10) = 42.9, ****p < 0.0001, when the hyperalgesia in the Gαi3 AS-ODN-treated and the SE-ODN-treated groups is compared at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). However, prolongation of PGE2-induced hyperalgesia was not affected by the treatment with Gαi3 AS-ODN in the systemic sub-AD morphine-treated group (D: F(1,10) = 0.04, p = 0.85, when hyperalgesia was compared between the Gαi3 SE-ODN-treated and AS-ODN-treated groups at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). These findings indicate that Gαi3 plays a role in hyperalgesia induced by both sub-AD fentanyl and morphine. However, priming induced by sub-AD fentanyl, but not sub-AD morphine, is dependent on Gαi3 (n = 6 paws/6 rats/group).