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. 2022 Feb 16;42(7):1196-1210.
doi: 10.1523/JNEUROSCI.1982-21.2021. Epub 2021 Dec 29.

Contribution of G-Protein α-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine

Dionéia Araldi  1 , Ivan J M Bonet  2 , Paul G Green  2   3 , Jon D Levine  1   4
Affiliations

Contribution of G-Protein α-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine

Dionéia Araldi et al. J Neurosci. .

Abstract

While opioids produce both analgesia and side effects by action at μ-opioid receptors (MORs), at spinal and supraspinal sites, the potency of different opioids to produce these effects varies. While it has been suggested that these differences might be because of bias for signaling via β-arrestin versus G-protein α-subunits (Gα), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gαi/o subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gαi2, Gαi3, and Gαo markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Gαi1, as well as Gαi2 and Gαi3, but not Gαo, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gαi1 and Gαi2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Gαi1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E2-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gαi3 and Gαo AS-ODN-treated rats, respectively. In contrast, none of the Gαi/o AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gαi/o subunits is necessary for the analgesia and side effects of two of the most clinically used opioid analgesics. The design of opioid analgesics that demonstrate selectivity for individual Gαi/o may produce a more limited range of side effects and enhanced analgesia.SIGNIFICANCE STATEMENT Biased μ-opioid receptor (MOR) agonists that preferentially signal through G-protein α-subunits over β-arrestins have been developed as an approach to mitigate opioid side effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense to different Gαi/o subunits play a role in hyperalgesia and analgesia induced by subanalgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G-protein α-subunits.

Keywords: G-protein; analgesia; fentanyl; hyperalgesic priming; morphine; opioid-induced hyperalgesia.

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Figures

Figure 1.
Figure 1.
Role of Gi-protein α1 subunit (Gαi1) in OIH and hyperalgesic priming produced by systemic sub-AD fentanyl and morphine. Rats received intrathecal (i.t.) injection of AS-ODN (120 μg/20 μl/d, i.t.) or SE-ODN (120 μg/20 μl/d, i.t.) to Gαi1 mRNA for 3 consecutive days. A, B, On the fourth day, at which time mechanical nociceptive threshold was not different from the pre-ODN baseline (A: SE-ODN-treated group: t(5) = 0.5; p = 0.64; AS-ODN-treated group: t(5) = 0.82; p = 0.45; B: SE-ODN-treated group: t(5) = 2.17; p = 0.08; AS-ODN-treated group: t(5) = 0.62; p = 0.56 when the mechanical nociceptive threshold is compared before and ∼17 h 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 injected and the mechanical nociceptive threshold was evaluated 1 h later. Gαi1 AS-ODN did not affect sub-AD fentanyl-induced hyperalgesia (F(1,10) = 1.94, p = 0.19, when hyperalgesia was compared between the Gαi1 SE-ODN- and AS-ODN-treated groups 1 h after systemic sub-AD fentanyl; two-way repeated-measures ANOVA followed by Bonferroni post hoc test; A). However, in the Gαi1 AS-ODN-treated group, OIH produced by sub-AD morphine was markedly attenuated (F(1,10) = 189.4, ****p < 0.0001, when the hyperalgesia in the Gαi1 SE-ODN- and the AS-ODN-treated groups is compared at 1 h after systemic sub-AD morphine; two-way repeated-measures ANOVA followed by Bonferroni post hoc test; B). At the end of the fourth day, rats again received intrathecal Gαi1 AS- 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) = 1.58; p = 0.18; AS-ODN-treated group that received sub-AD fentanyl: t(5) = 0.39; p = 0.71; D: SE-ODN-treated group: t(5) = 0.88; p = 0.42; AS-ODN-treated group that received sub-AD morphine: t(5) = 0.2; p = 0.85 when the mechanical nociceptive threshold is compared before and 5 d after systemic sub-AD opioid administration; 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. Treatment with Gαi1 AS-ODN did not prevent PGE2-induced prolonged hyperalgesia in either fentanyl-treated (C) or morphine-treated (D) groups (C: F(1,10) = 2.12, p = 0.17; D: F(1,10) = 1.02, p = 0.34, when the hyperalgesia in the Gαi1 SE-ODN- and the AS-ODN-treated groups is compared at the fourth hour after intradermal PGE2 administration; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). These findings support the suggestion that Gαi1 plays a role in OIH produced by systemic sub-AD morphine, but not fentanyl, and is not involved in hyperalgesic priming produced by sub-AD fentanyl or morphine (n = 6 paws/6 rats/group).
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).
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).
Figure 4.
Figure 4.
Role of Gαo in hyperalgesia and hyperalgesic priming induced 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 Gαo mRNA daily for 3 consecutive days. On the fourth day, at which time the mechanical nociceptive threshold was not different from the pre-ODN baselines (A: SE-ODN-treated group: t(5) = 0.67; p = 0.53; AS-ODN-treated group: t(5) = 0.65; p = 0.54; B: SE-ODN-treated group: t(5) = 0.74; p = 0.49; AS-ODN-treated group: t(5) = 1.66; p = 0.15, when the mechanical nociceptive threshold is compared before and ∼17 h 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 the mechanical nociceptive threshold was evaluated 1 h later. In the group of rats treated with Gαo AS-ODN, systemic sub-AD fentanyl-induced hyperalgesia was prevented (A, F(1,10) = 53.3, ****p < 0.0001, when the hyperalgesia in the Gαo SE-ODN-treated and the AS-ODN-treated groups was compared at 1 h after systemic sub-AD fentanyl; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). However, systemic sub-AD morphine-induced hyperalgesia was not affected by the treatment with Gαo AS-ODN (B, F(1,10) = 0.24, p = 0.63, when the hyperalgesia in the Gαo SE-ODN-treated and the AS-ODN-treated groups was compared at 1 h after systemic sub-AD morphine; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). At the end of the fourth day, rats again received intrathecal Gαo AS-ODN or SE-ODN. Five days after systemic sub-AD fentanyl and morphine, when the mechanical nociceptive threshold was not different from preopioid baselines (C: SE-ODN-treated group: t(5) = 0.75; p = 0.48; AS-ODN-treated group that received sub-AD fentanyl: t(5) = 2.15; p = 0.08; D: SE-ODN-treated group: t(5) = 0.68; p = 0.53; AS-ODN-treated group that received sub-AD morphine: t(5) = 1.90; p = 0.11, 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 administered and the mechanical nociceptive threshold was evaluated 30 min and 4 h later. Treatment with Gαo AS-ODN did not prevent the prolongation of PGE2-induced hyperalgesia in both fentanyl-treated (C) and morphine-treated (D) groups of rats (C: F(1,10) = 2.15, p = 0.17; D: F(1,10) = 0.18, p = 0.68, when the hyperalgesia in the Gαo SE-ODN-treated and the AS-ODN-treated groups is compared at the fourth hour after intradermal PGE2; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). These findings support the suggestion that the Gαo subunit plays a role in OIH produced by systemic sub-AD fentanyl, but not morphine, and is not involved in hyperalgesic priming produced by sub-AD fentanyl and morphine. (n = 6 paws/6 rats/group).
Figure 5.
Figure 5.
Role of Gαi1 in systemic AD fentanyl- and morphine-induced analgesia and priming. Rats received intrathecal injections of AS-ODN (120 μg in 20 μl/d, i.t.) or SE-ODN (120 μg in 20 μl/d, i.t.) against Gαi1 mRNA, daily for 3 consecutive days. On the fourth day, AD fentanyl (A, 0.03 mg/kg, s.c.) or morphine (B, 3 mg/kg, s.c.) was administered and the mechanical nociceptive threshold was evaluated 1 h later. Treatment with Gαi1 AS-ODN increased analgesia induced by systemic AD fentanyl (A), while it decreased AD morphine-induced analgesia (B), compared with their respective Gαi1 SE-ODN-treated groups (A: t(10) = 3.24, ** p = 0.0088; B: t(10) = 4.81, *** p = 0.0007, when the analgesia in the Gαi1 AS-ODN-treated and the SE-ODN-treated groups is compared at 1 h after systemic AD fentanyl and morphine; unpaired Student's t test). At the end of the fourth day, rats again received intrathecal Gαi1 AS-ODN or SE-ODN. Five days after systemic AD fentanyl and morphine administration, at which time the mechanical nociceptive threshold was not different from preopioid baselines (C: SE-ODN-treated group: t(5) = 0.39, p = 0.71; AS-ODN-treated group that received systemic AD fentanyl: t(5) = 1.4, p = 0.22; D: SE-ODN-treated group: t(5) = 1.0, p = 0.36; AS-ODN-treated group that received systemic AD morphine: t(5) = 0.58, p = 0.59, when the mechanical nociceptive threshold is compared before and 5 d after systemic AD opioids; paired Student's t test), PGE2 (100 ng/5 μl, i.d.) was administered and the mechanical nociceptive threshold was evaluated 30 min and 4 h later. Prolongation of PGE2-induced hyperalgesia was not affected by treatment with Gαi1 AS-ODN in both AD fentanyl-treated (C) and morphine-treated (D) groups of rats (C: F(1,10) = 1.28, p = 0.28; D: F(1,10) = 0.13, p = 0.72, when the hyperalgesia in the Gαi1 SE-ODN-treated and the AS-ODN-treated groups is compared at the fourth hour after intradermal PGE2 administration; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). These findings support the suggestion that Gαi1 plays a role in analgesia, but not in hyperalgesic priming, produced by AD fentanyl and morphine (n = 6 paws/6 rats/group).
Figure 6.
Figure 6.
Role of Gαi2 in analgesia and hyperalgesic priming induced by systemic analgesic dose 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, daily for 3 consecutive days. Approximately 17 h after the third injection of ODNs, AD fentanyl (A: 0.03 mg/kg, s.c.) or morphine (B: 3 mg/kg, s.c.) was administered and the mechanical nociceptive threshold was evaluated 1 h later. Treatment with Gαi2 AS-ODN increased analgesia induced by AD fentanyl (A); however, it did not affect analgesia induced by AD morphine (B), when compared with the SE-ODN-treated group (A: t(10) = 5.07, ***p = 0.0005; B: t(10) = 0.96, p = 0.36, when the analgesia in the Gαi2 AS-ODN-treated and the SE-ODN-treated groups is compared at 1 h after systemic AD fentanyl and morphine, respectively; unpaired Student's t test). Rats again received Gαi2 AS-ODN or SE-ODN later on the fourth day. Five days after AD opioids, at which time mechanical nociceptive threshold was not different from preopioid baselines (C: SE-ODN-treated group: t(5) = 2.5, p = 0.06; AS-ODN-treated group that received AD fentanyl: t(5) = 0.67; p = 0.53; D: SE-ODN-treated group: t(5) = 1.0, p = 0.36; AS-ODN-treated group that received AD morphine: t(5) = 0.12, p = 0.91, when the mechanical nociceptive threshold is compared before and 5 d after systemic AD opioids; paired Student's t test), PGE2 (100 ng/5 μl, i.d.) was administered and the mechanical nociceptive threshold was evaluated 30 min and 4 h later. In both the Gαi2 AS-treated and SE-ODN-treated groups, the prolongation of PGE2-induced hyperalgesia was present 5 d after systemic AD fentanyl and morphine (C and D, respectively; C: F(1,10) = 0.68, p = 0.43; D: F(1,10) = 2.84, p = 0.12, when the hyperalgesia in the Gαi2 AS-ODN-treated and the SE-ODN-treated groups is compared at the fourth hour after intradermal PGE2 administration; two-way repeated-measures ANOVA followed by Bonferroni's post hoc test). Our data support the suggestion that the Gαi2 subunit plays a role in analgesia produced by AD fentanyl, but not morphine; also, hyperalgesic priming produced by AD fentanyl and morphine is not Gαi2 dependent (n = 6 paws/6 rats/group).
Figure 7.
Figure 7.
Role of Gαi3 in analgesia and hyperalgesic priming induced by systemic AD fentanyl and morphine. Rats received intrathecal injections of AS-ODN (120 μg in 20 μl/d, i.t.) or SE-ODN (120 μg in 20 μl/day, i.t.) against Gαi3 mRNA, daily for 3 consecutive days. On the fourth day, ∼17 h after the third injection of ODNs, systemic AD fentanyl (A: 0.03 mg/kg, s.c.) or morphine (B: 3 mg/kg, s.c.) was injected and mechanical nociceptive threshold evaluated 1 h later. Treatment with Gαi3 AS-ODN did not affect the analgesia produced by either AD fentanyl (A) or morphine (B), measured 1 h after their administration, as observed in the Gαi3 SE-ODN-treated group (A: t(10) = 0.054; ***p = 0.96; B: t(10) = 0.51, p = 0.62, when the analgesia in the Gαi3 AS-ODN-treated and the SE-ODN-treated groups is compared at 1 h after systemic AD fentanyl and morphine, respectively; unpaired Student's t test). At the end of the fourth day, rats again received intrathecal Gαi3 AS-ODN or SE-ODN. Five days after systemic AD fentanyl and morphine, at which time the mechanical nociceptive threshold was not different from preopioid baseline levels (C: SE-ODN-treated group: t(5) = 1.38, p = 0.23; AS-ODN-treated group that received systemic AD fentanyl: t(5) = 1.06, p = 0.34; D: SE-ODN-treated group: t(5) = 2.0, p = 0.1; AS-ODN-treated group that received systemic AD morphine: t(5) = 0.72, p = 0.5, when the mechanical nociceptive threshold is compared before and 5 d after systemic 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 Gαi3 AS-ODN-treated and SE-ODN-treated groups, the prolongation of PGE2-induced hyperalgesia was present 5 d after systemic AD fentanyl and morphine (C and D, respectively; C: F(1,10) = 0.58, p = 0.46; D: F(1,10) = 0.1, p = 0.75, 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). These findings support the suggestion that Gαi3 did not play a role in analgesia and hyperalgesic priming induced by AD fentanyl or morphine (n = 6 paws/6 rats/group).
Figure 8.
Figure 8.
Role of Gαo in analgesia and hyperalgesic priming induced by systemic AD fentanyl and morphine. Rats received intrathecal injections of AS-ODN (120 μg in 20 μl/d, i.t.) or SE-ODN (120 μg in 20 μl/d, i.t.) against Gαo mRNA, daily for 3 consecutive days. On the fourth day, AD fentanyl (A: 0.03 mg/kg, s.c.) or morphine (B: 3 mg/kg, s.c.) was administered and the mechanical nociceptive threshold was evaluated 1 h later. In the groups of rats treated with Gαo AS-ODN, systemic AD fentanyl (A), and morphine (B) induced analgesia that was not different when compared with their respective Gαo SE-ODN-treated groups (A: t(10) = 0.13, p = 0.90; B: t(10) = 0.005, p = 0.99, when the analgesia in the Gαo AS-ODN-treated and the SE-ODN-treated groups is compared at 1 h after systemic AD fentanyl and morphine, respectively; unpaired Student's t test). At the end of the fourth day, rats again received Gαo AS-ODN or SE-ODN. Five days after systemic AD fentanyl and morphine, when the mechanical nociceptive threshold was not different from the preopioids baselines (C: SE-ODN-treated group: t(5) = 2.03; p = 0.09; AS-ODN-treated group that received AD fentanyl: t(5) = 1.26; p = 0.26; D: SE-ODN-treated group: t(5) = 1.1, p = 0.32; AS-ODN-treated group that received AD morphine: t(5) = 1.52, p = 0.19, when the mechanical nociceptive threshold is compared before and 5 d after systemic 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. Treatment with Gαo AS-ODN markedly attenuates PGE2-induced prolonged hyperalgesia in rats that received AD fentanyl (C: F(1,10) = 23.6, *** p = 0.0007, when the hyperalgesia in the Gαo 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, the prolongation of PGE2-induced hyperalgesia was not affected by treatment with Gαo AS-ODN in the AD morphine-treated group (D: F(1,10) = 2.89, p = 0.12, when hyperalgesia was compared between the Gαo 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 analgesia produced by systemic AD fentanyl and morphine is not Gαo subunit dependent; however, the Gαo subunit does play a role in hyperalgesic priming induced by AD fentanyl, but not morphine (n = 6 paws/6 rats/group).
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