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

Figure 2.

Figure 2.

Role of Gαi2 in hyperalgesia and hyperalgesic priming produced by systemic sub-AD fentanyl and morphine. Rats received injections of AS-ODN (120 μg/20 μl/d, i.t.) or SE-ODN (120 μg/20 μl/d, i.t.) against Gαi2 mRNA, for 3 consecutive days. A, B, Approximately 17 h after the third injection, at which time the mechanical nociceptive threshold was not different from pre-ODN baseline levels (A: SE-ODN-treated group: t(5) = 0.41, p = 0.70; AS-ODN-treated group: t(5) = 0.56; p = 0.57; B: SE-ODN-treated group: t(5) = 0.15, p = 0.89; AS-ODN-treated group: t(5) = 0.13, p = 0.90, when the mechanical nociceptive threshold is compared before and after the third 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 mechanical nociceptive threshold was evaluated 1 h later. Treatment with Gαi2 AS-ODN prevented hyperalgesia induced by both sub-AD fentanyl (A) and morphine (B), when it was compared with the SE-ODN-treated group (A: F(1,10) = 75.5, ****p < 0.0001; B: F(1,10) = 298.3, ****p < 0.0001, when the hyperalgesia in the Gαi2 SE-ODN-treated and the AS-ODN-treated groups is compared at 1 h after systemic sub-AD fentanyl and morphine; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). Rats again received intrathecal Gαi2 AS- or SE-ODN on the fourth day. C, D, Five days after sub-AD opioids, at which time the mechanical nociceptive threshold was not different from preopioid baseline (C: SE-ODN-treated group: t(5) = 1.0, p = 0.36; AS-ODN-treated group that received sub-AD fentanyl: t(5) = 0.54, p = 0.61; D: SE-ODN-treated group: t(5) = 0.73, p = 0.49; AS-ODN-treated group that received sub-AD morphine: t(5) = 0.59, p = 0.57, when the mechanical nociceptive threshold is compared before and 5 d after systemic sub-AD opioids; paired Student's t test), PGE2 (100 ng/5 μl, i.d.) was injected and the mechanical nociceptive threshold was evaluated 30 min and 4 h later. In both the Gαi2 AS-ODN-treated and SE-ODN-treated groups, the prolongation of PGE2 hyperalgesia was present 5 d after systemic sub-AD fentanyl and morphine (C and D, respectively; C: F(1,10) = 0.11, p = 0.74; D: F(1,10) = 0.50, p = 0.49, when the hyperalgesia in the Gαi2 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). Our data indicate that OIH, but not priming, produced by systemic sub-AD fentanyl and morphine is Gαi2 dependent (n = 6 paws/6 rats/group).