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. 2015 Sep 9;35(36):12502-17.
doi: 10.1523/JNEUROSCI.1673-15.2015.

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

Dioneia Araldi  1 , Luiz F Ferrari  1 , Jon D Levine  2
Affiliations

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

Dioneia Araldi et al. J Neurosci. .

Abstract

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.

Keywords: chronic pain; hyperalgesia; hyperalgesic priming; mu-opioid receptor; β/γ subunit.

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Figures

Figure 1.
Figure 1.
Repeated exposure to DAMGO induces acute mechanical hyperalgesia and prolongation of PGE2 hyperalgesia in male rats. A, Male rats received repeated (hourly, ×4) intradermal injections of vehicle (control, black bars) or DAMGO (1 μg, white bars) on the dorsum of the hindpaw and the mechanical nociceptive threshold was evaluated at the injection site 30 min after the first, third, and fourth administration by the Randall–Sellitto paw-withdrawal test. Significant hyperalgesia was observed after a fourth injection of DAMGO, but not to DAMGO in the vehicle-treated paws (F(1,20) = 18.72; ***p < 0.001, when both groups are compared; two-way repeated-measures ANOVA followed by Bonferroni post hoc test); B, A separate group of rats received repeated (hourly, ×3) intradermal injection of DAMGO (1 μg) on the dorsum of the hindpaw. A fourth injection 1 h after the third dose of DAMGO, vehicle (gray bars), or PGE2 (100 ng, white bars) was performed at the same site and the mechanical nociceptive threshold was evaluated 30 min and 4 h later. We observed that, whereas injection of vehicle did not induce significant change in the mechanical threshold, the injection of PGE2 induced hyperalgesia that was still present at the fourth hour (F(1,20) = 280.56; ***p < 0.0001, when both groups are compared; two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating the presence of priming; C, Rats that were treated with 4 injections of vehicle (black bars) or DAMGO (white bars) 1 week before received PGE2 (100 ng) injected at the same site. Mechanical nociceptive threshold was then evaluated 30 min and 4 h later. By the time that PGE2 was injected, the mechanical nociceptive thresholds were not different from preinjection control baseline (t(5) = 0.6956; p = 0.5177, for the vehicle group; t(5) = 1.320; p = 0.2441, for the DAMGO group; paired Student's t test). In both groups, PGE2 induced significant hyperalgesia. However, whereas in the vehicle-treated group, the effect of PGE2 was no longer present at 4 h, in the group previously treated with DAMGO (hourly, ×3), the hyperalgesia induced by PGE2 was still present, indicating the presence of priming (***p < 0.0001 when both groups are compared at the fourth hour, two-way repeated-measures ANOVA followed by Bonferroni post hoc test). D, Thirty-eight days after the vehicle (×3) or DAMGO (×3) treatments (no difference in the average mechanical nociceptive thresholds from pretreatments levels was observed: p = 0.0706 for the vehicle, t(5) = 2.291; p = 0.1613 for the DAMGO group, t(5) = 1.643; paired Student's t test), PGE2 was injected again at the same site. We observed that it produced prolonged hyperalgesia in the group previously treated with DAMGO (×3), but not in the vehicle-treated control group, and this was significant 4 h after injection (***p < 0.0001, when both groups are compared, two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating that the repeated injection of DAMGO produced long-term plastic changes in nociceptors. n = 6 paws per group.
Figure 2.
Figure 2.
Rapid onset of DAMGO hyperalgesia and long-term persistence of type II priming. A, Mechanical nociceptive threshold was evaluated 1, 3, 5, 10, 15, 20, and 30 min after a fourth injection of DAMGO (1 μg) on the dorsum of the hindpaw. Significant hyperalgesia was already observed 5 min after the fourth injection (*p < 0.05 and ***p < 0.005, compared with the baseline (BL), paired Student's t test). B, Rats that were treated with repeated injection of DAMGO (1 μg/h ×4) 1 week before received, at the same site, an injection of DAMGO (1 μg, white bars) or vehicle (black bars). Mechanical hyperalgesia, evaluated 30 min and 4 h after injection, was observed only in the paws previously treated with repeated injection of DAMGO, showing the persistence of the changes in the nociceptor produced by the repeated stimulation of the MOR (F(1,20) = 88.69; ***p < 0.001 and *p < 0.005, two-way repeated-measures ANOVA followed by Bonferroni post hoc test; n = 6 paws per group).
Figure 3.
Figure 3.
Type II priming is not dependent on PKCε or local protein translation. Male rats that were treated with repeated intradermal administration of DAMGO (1 μg/h ×4) on the dorsum of the hindpaw received 1 week later an injection of PGE2 (100 ng) at the same site in the presence of vehicle (control, black bars), PKCε inhibitor (1 μg, gray bars), or the inhibitor of protein translation cordycepin (1 μg, white bars) administered 10 min before. Mechanical nociceptive threshold was evaluated 30 min and 4 h after PGE2. We observed no difference between the groups in the prolongation of the PGE2-induced hyperalgesia (F(4,30) = 0.72; p = 0.5861, two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating that the neuroplasticity induced by previous repeated injection of DAMGO is not dependent on PKCε or local protein translation. n = 6 paws per group.
Figure 4.
Figure 4.
Role of PKA in type II priming. A, Rats were treated with intradermal injection of vehicle (control, black bars) or H-89 (1 μg, white bars) on the dorsum of the hindpaw. Ten minutes later, 4 injections of DAMGO (1 μg, hourly) were performed in both groups of rats. We observed, in the group pretreated with H-89, significant attenuation of the mechanical hyperalgesia induced by the fourth injection of DAMGO compared with the control group (F(1,10) = 18.52; ***p = 0.0016, two-way repeated-measures ANOVA followed by Bonferroni post hoc test); B, Rats were treated with intradermal injection of vehicle or H-89 (1 μg) on the dorsum of the hindpaw. Ten minutes later, 3 injections of DAMGO (1 μg/h ×3) were performed. One hour after the third injection of DAMGO, PGE2 (100 ng) was injected at the same site and the mechanical hyperalgesia was evaluated 30 min and 4 h later. Both at 30 min and 4 h, significant attenuation of the mechanical hyperalgesia induced by PGE2 was observed in the group pretreated with H-89 (F(1,10) = 189.86, ***p < 0.0001, vehicle vs H-89 groups; two-way repeated-measures ANOVA followed by Bonferroni post hoc test); C, Six days later, a time point when the mechanical nociceptive threshold was not different from the pretreatment levels (t(5) = 2.000; p = 0.1019, for the control group; t(5) = 2.169; p = 0.0822, for the H-89 group; paired Student's t test), PGE2 (100 ng) was injected at the same site and the mechanical hyperalgesia was evaluated 30 min and 4 h later. Although PGE2-induced hyperalgesia was present 30 min after injection, in the group previously treated with H-89, it was significantly reduced at the fourth hour (F(1,20) = 15.67, ***p < 0.001, when both groups are compared at the fourth hour; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). To determine whether type II priming was permanently prevented by H-89, PGE2 was injected again at the same site 30 d later. At this time, we observed that the hyperalgesia induced by PGE2 was prolonged in both groups; D, Rats received repeated (hourly, ×4) intradermal injection of DAMGO (1 μg) on the dorsum of the hindpaw. Six days later, when the mechanical thresholds were no longer different from pre-DAMGO levels (t7 = 0.7593; p = 0.4819, paired Student's t test), vehicle (control, black bars) or H-89 (1 μg, white bars) was injected at the same site, followed 10 min later by PGE2 (100 ng). Although PGE2-induced hyperalgesia was still present 4 h later in the group that received vehicle, in the group treated with H-89, it was attenuated at both time points (F(1,28) = 585.86 ***p < 0.0001, two-way repeated-measures ANOVA followed by Bonferroni post hoc test). E, Left, Six days later, when PGE2 was injected again at the same site, the mechanical hyperalgesia in the group that had previously received H-89 (6 d before, white bars) was still significantly attenuated at both 30 min and 4 h (F(2,18) = 133.63, ***p < 0.0001, H-89 vs control groups, two-way repeated-measures ANOVA followed by Bonferroni post hoc test). Right, To determine whether the treatment with H-89 had permanently reversed the type II priming, PGE2 was again injected at the same site 30 d later (gray bars). In this case, however, we observed that PGE2 produced significant hyperalgesia that was present 30 min and 4 h after injection in both groups, indicating that type II priming was present. n = 6 paws per group.
Figure 5.
Figure 5.
Repeated exposure to DAMGO induces acute mechanical hyperalgesia and prolongation of PGE2 hyperalgesia in female rats. Left, Female rats received repeated hourly (×4) intradermal injections of DAMGO (1 μg) on the dorsum of the hindpaw. The mechanical nociceptive threshold was evaluated before and 30 min after the first, third, and fourth administration. We observed significant hyperalgesia after the third and fourth injections of DAMGO (***p = 0.0005 and *p < 0.0001, respectively, third and fourth injections vs baseline threshold; **p = 0.007 third vs fourth injection thresholds, paired Student's t test); Right, One week later, when the mechanical thresholds were no longer different from pre-DAMGO levels (p = 0.3939, paired Student's t test), PGE2 (100 ng) was again injected at the same site and mechanical hyperalgesia was evaluated 30 min and 4 h later. One-way ANOVA followed by Bonferroni post test showed that PGE2 induced significant hyperalgesia that was still present 4 h after its injection (***p < 0.0001, compared with the baseline pre-PGE2 injection). Together, these data demonstrate that, as in males, repeated injection of DAMGO also produces neuroplasticity in female rats, with a more rapid onset in the female. n = 6 paws per group.
Figure 6.
Figure 6.
Effect of elimination of IB4+ nociceptors on type II priming. Left, Male rats were treated with vehicle (control, black bars) or IB4-saporin (3.2 μg/20 μl; white bars) by intrathecal injection. Two weeks later, DAMGO (1 μg) was injected (hourly, ×4) on the dorsum of the hindpaw. Although, in the vehicle-treated group, the mechanical hyperalgesia developed after the fourth injection of DAMGO, in the IB4-saporin-treated group, it was already present after the third injection, significantly further increasing after the fourth injection (F(1,20) = 33.11; ***p < 0.001, when both groups are compared; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). Right, One week later, when the mechanical thresholds were not different from the pre-DAMGO baseline (t(5) = 0.9035; p = 0.4077, for the control group; t(5) = 1.419; p = 0.2150, for the IB4-saporin group, paired Student's t test), PGE2 (100 ng) was injected at the same site on the dorsum of the hindpaw and the mechanical hyperalgesia was evaluated 30 min and 4 h later. Two-way repeated-measures ANOVA followed by Bonferroni post hoc test showed PGE2-induced hyperalgesia at 30 min, which was still present at the fourth hour after injection in both groups, with no significant (NS) difference between the groups (p > 0.05, two-way repeated-measures ANOVA followed by Bonferroni post hoc test). These data support the suggestion that IB4+ nociceptors do not contribute to the prolonged hyperalgesia induced by PGE2 observed in type II priming. n = 6 paws per group.
Figure 7.
Figure 7.
Second messengers involved in type II priming: PLC-β3 and Src. A, Left, Rats were treated with daily spinal intrathecal injections of MM-ODN (black bars) or AS-ODN (white bars) for PLC-β3 mRNA for 3 consecutive days. On the fourth day, repeated (hourly, ×4) intradermal injections of DAMGO (1 μg) on the dorsum of the hindpaw were performed and the mechanical nociceptive threshold was evaluated 30 min after the fourth DAMGO injection. We observed that, in the MM-ODN-treated group, but not in the AS-ODN-treated group, the fourth injection of DAMGO produced significant mechanical hyperalgesia (***p = 0.0009, paired Student's t test, when both groups are compared), suggesting a role for PLC-β3 in DAMGO hyperalgesia. ODN treatment continued for 2 more days and, at a time point when the mechanical thresholds were not different from the pre-DAMGO levels (t(5) = 0.9918; p = 0.3668, for the MM-ODN group; t(5) = 2.490; p = 0.0551, for the AS-ODN group; paired Student's t test), PGE2 (100 ng) was administered in both groups. Evaluation of the mechanical thresholds 30 min and 4 h after injection showed that, whereas PGE2 induced hyperalgesia that was still present 4 h later in the group treated with MM-ODN, in the group treated with AS-ODN against PLC-β3, the hyperalgesia was significantly attenuated at both time points (F(1,20) = 128.33; ***p < 0.0001, two-way repeated-measures ANOVA followed by Bonferroni post hoc test). Right, To determine whether the reversal of type II priming by treatment with AS-ODN was permanent, PGE2 was injected again in the same site 12 d after the last ODN injection. We observed that PGE2-induced mechanical hyperalgesia was still present at the fourth hour, indicating the presence of type II priming. B, Rats were treated with intradermal injection of vehicle (control, black bars) or SU6656 (1 μg, white bars). Ten minutes later, repeated injections of DAMGO (1 μg) were performed on the dorsum of the hindpaw. No difference in the mechanical hyperalgesia after the fourth injection of DAMGO was observed when the groups treated with SU6656 or vehicle were compared (nonsignificant, NS; paired Student's t test). Two days later, when the mechanical thresholds were not different from pretreatment levels (t(5) = 2.5690; p = 0.0501, for the control group; t(5) = 0.5423; p = 0.6109, for the SU6656 group; paired Student's t test), PGE2 (100 ng) was injected at the same site and mechanical hyperalgesia was evaluated 30 min and 4 h later. In the group previously treated with SU6656, PGE2-induced hyperalgesia was almost completely inhibited at the fourth hour (F(1,20) = 100.00; ***p < 0.0001, when both groups are compared at the 30 min and fourth hour, respectively; two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating a role of Src in type II priming. C, Male rats received repeated (hourly, ×4) intradermal injections of DAMGO (1 μg) on the dorsum of the hindpaw. Four days later, when the mechanical thresholds were not different from the pre-DAMGO levels (t(5) = 0.8500; p = 0.4341, for the control group; t(5) = 1.356; p = 0.2332, for the SU6656 group; paired Student's t test), vehicle (control) or the Src inhibitor SU6656 (1 μg) was injected at the same site, followed 10 min later by PGE2 (100 ng). Although PGE2 induced significant hyperalgesia that was still present when evaluated 4 h later in the vehicle-treated group, in the group treated with SU6656, PGE2-induced hyperalgesia was attenuated at the fourth hour (F(1,20) = 184.31; **p < 0.01 and ***p < 0.001, two-way repeated-measures ANOVA followed by Bonferroni post hoc). n = 6 paws per group.
Figure 8.
Figure 8.
Some second messengers not involved in type II priming. The groups of rats that had been treated with repeated (hourly, ×4) intradermal injections of DAMGO (1 μg) on the dorsum of the hindpaw 6 d before received, in a dose of 1 μg at the same site, injection of vehicle (control, black bars) or of the inhibitors of intracellular messengers wortmannin (PI3K), Z-VAD-FMK (caspase), U-73122 (PLCγ), l-NMMA (nitric oxide synthase), and quin-2 (calcium). Ten minutes later, PGE2 (100 ng) was injected and mechanical hyperalgesia was evaluated 30 min and 4 h after PGE2. In all groups, we observed that PGE2 induced significant hyperalgesia that was still present when evaluated 4 h after injection, ruling out the involvement of these second messengers in type II priming. n = 6 paws per group.
Figure 9.
Figure 9.
Role of the inhibitory G-protein αi subunit in type II priming. A, Rats received an intradermal injection of vehicle (control, black bars) or PTX (1 μg, white bars) on the dorsum of the hindpaw. Thirty minutes later, DAMGO (1 μg) was injected (hourly, ×4) in the same site. We observed significant mechanical hyperalgesia after the fourth injection of DAMGO, with no significant (NS) difference between groups (t(5) = 0.1075, p = 0.9186, control vs PTX groups, unpaired Student's t test), demonstrating that the αi subunit does not play a role in the hyperalgesia induced by repeated injection of DAMGO. Four days later, when the mechanical thresholds were not different from the prevehicle/PTX injection levels (t(5) = 0.3384; p = 0.7488 and t(5) = 0.5547; p = 0.6030, respectively, paired Student's t test), rats received intradermal injection of PGE2 (100 ng) in the same site and mechanical hyperalgesia was evaluated 30 min and 4 h later. No significant difference was observed in PGE2-induced mechanical hyperalgesia evaluated 30 min and 4 h after injection (F(1,20) = 0.17; p = 0.6859, when comparing both groups; NS, p > 0.05, two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating that the αi subunit does not play a role in the prolongation of PGE2 hyperalgesia in type II priming; B, Rats received repeated (hourly, ×4) intradermal injections of the G-protein αi subunit peptide activator mastoparan (1 μg) on the dorsum of the hindpaw. The mechanical nociceptive threshold was evaluated before and 30 min after the first and fourth administrations. Unpaired Student's t test showed that the injection of mastoparan did not induce significant change in the mechanical nociceptive threshold (p = 1.0000) even after 4 hourly administrations compared with the control group. Four days later, PGE2 (100 ng) was injected at the same site and mechanical thresholds were evaluated after 30 min and 4 h. In both groups, we observed significant mechanical hyperalgesia induced by PGE2 30 min after injection (NS, p > 0.05) that was no longer present at the fourth hour (NS; F(1,20) = 2.14; p = 0.1747, when comparing both groups at the fourth hour after PGE2 injection; NS, p > 0.05), indicating that an activator of G-protein αi subunit does not induce priming. n = 6 paws per group.
Figure 10.
Figure 10.
Type II priming is dependent on the G-protein β/γ subunit. A, Rats were treated with intradermal injection of vehicle (control, black bars) or the G-protein β/γ inhibitor gallein (1 μg, white bars) on the dorsum of the hindpaw. Thirty minutes later, repeated injections (hourly, ×4) of DAMGO (1 μg) were performed at the same site and the mechanical nociceptive threshold was evaluated 30 min after the fourth administration. We observed significant mechanical hyperalgesia after the fourth injection of DAMGO in the group pretreated with vehicle, but not in the group pretreated with gallein (***p = 0.0001 when both groups are compared, paired Student's t test). Four days later, a time point when the mechanical thresholds were not different from preinjection levels (t(5) = 2.150; p = 0.0842, for the control group and t(5) = 1.530; p = 0.1852, for the gallein group; paired Student's t test), rats received intradermal injection of PGE2 (100 ng) at the same site and mechanical hyperalgesia was evaluated 30 min and 4 h later. Although in both groups PGE2-induced mechanical hyperalgesia was present 30 min after injection (NS, p > 0.05), in the gallein-treated group, it was markedly attenuated at the fourth hour (F(1,20) = 36.20, ***p < 0.0001, when control and gallein groups are compared at the fourth hour after PGE2 injection; two-way repeated-measures ANOVA followed by Bonferroni post hoc test). However, when PGE2 was injected again 8 d later, it produced mechanical hyperalgesia that was still present 4 h after injection, indicating that the inhibition of the induction of type II priming by gallein was reversible; B, Rats that were treated with repeated hourly (×4) injections of DAMGO on the dorsum of the hindpaw received vehicle (control, black bars) or gallein (1 μg, white bars) 4 d later at the same site followed 10 min later by PGE2 (100 ng). Average mechanical nociceptive thresholds before and 4 d after treatment with DAMGO were 122.7 ± 0.8 g and 120.3 ± 1.4 g, respectively, for the control and the gallein group. Paired Student's t test showed no difference between these values (t(5) = 0.6670; p = 0.5343 for the control group and t(5) = 0.7559; p = 0.4838 for the gallein group). Evaluation of the mechanical nociceptive threshold 30 min and 4 h after PGE2 showed significant attenuation of the hyperalgesia induced by PGE2 at both time points in the group treated with gallein (F(1,12) = 83.65, ***p < 0.0001 when both groups are compared, two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating that, in the setting of the neuroplasticity induced by repeated injections of DAMGO, PGE2-induced hyperalgesia depends on the G-protein β/γ subunit; C, Rats treated with intradermal injection of vehicle (5 μl, black bars) or gallein (1 μg, white bars) received PGE2 (100 ng) 30 min later at the same site. We observed significant mechanical hyperalgesia, evaluated 30 min after the injection of PGE2, in both groups (p > 0.05 control- vs gallein-treated groups, two-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating that the β/γ subunit is not involved in the hyperalgesic effect of PGE2 in the naive rat. n = 6 paws per group.
Figure 11.
Figure 11.
An activator of the G-protein β/γ subunit does not induce acute mechanical hyperalgesia or type II priming. Rats received repeated (hourly, ×4) intradermal injections of G-protein βγ peptide (1 μg; peptide activator of G-protein β/γ) on the dorsum of the hindpaw. The mechanical nociceptive threshold was evaluated before and 30 min after the first, third, and fourth administration. No significant difference in the mechanical threshold was observed 30 min after the first (p = 0.4838), third (p = 0.3632), or fourth (p = 0.1672) injection of G-protein βγ peptide compared with the preinjection level (paired Student's t test). One week later, PGE2 (100 ng) was injected at the same site and mechanical hyperalgesia was evaluated after 30 min and 4 h. The hyperalgesia induced by PGE2 was present 30 min after injection (***p < 0.0001 vs baseline; one-way repeated-measures ANOVA followed by Bonferroni post hoc test), but had disappeared 4 h later (NS, p > 0.05 vs baseline), indicating that repeated activation of G-protein β/γ does not induce type II priming. n = 6 paws per group.
Figure 12.
Figure 12.
Changes in PKA signaling contribute to the prolongation of PGE2-induced hyperalgesia in type II priming. A, Rats received 3 hourly intradermal injections of vehicle or DAMGO (1 μg) on the dorsum of the hindpaw. 8-bromo cAMP (1 μg) was injected at the same site 1 h later and mechanical hyperalgesia was evaluated after 30 min and 4 h. 8-bromo cAMP produced mechanical hyperalgesia in both groups at 30 min. However, in the group previously treated with DAMGO, it was significantly enhanced and prolonged and still present after 4 h, as opposed to the vehicle-treated group (F(1,20) = 96.82; ***p < 0.0001, when comparing both groups; two-way repeated-measures ANOVA followed by Bonferroni post hoc test), suggesting an increased activation of PKA signaling by repeated MOR activation; B, Rats received 3 hourly intradermal injections of DAMGO (1 μg) on the dorsum of the hindpaw and a fourth injection of 8-bromo cAMP (1 μg) at the same site. Significant mechanical hyperalgesia was observed 30 min later. Injection of H-89 (1 μg) 1 h after 8-bromo cAMP inhibited the ongoing hyperalgesia evaluated 3 h later that was produced by the previous treatment with repeated injections of DAMGO (NS, p > 0.05 vs baseline; one-way repeated-measures ANOVA followed by Bonferroni post hoc test), indicating a role of PKA in the increased activation of the cAMP signaling pathway produced by repeated MOR agonist administration. n = 6 paws per group.
Figure 13.
Figure 13.
Proteasome inhibitor does not affect type II priming. A, Rats were treated with intradermal injection of the proteasome inhibitor MG-132 (1 μg) on the dorsum of the hindpaw. Thirty minutes later, repeated (hourly, ×4) injections of DAMGO (1 μg) were performed at the same site and the mechanical nociceptive threshold was evaluated 30 min after the fourth administration. Significant mechanical hyperalgesia was observed after the fourth injection of DAMGO in the group pretreated with MG-132 compared with baseline (**p = 0.0069, paired Student's t test). B, A different group of rats was treated with intradermal injection of MG-132 (1 μg) and, after 30 min, repeated (hourly, ×3) injections of DAMGO (1 μg) were performed at the same site. One hour after the third injection of DAMGO, PGE2 (100 ng) was injected and mechanical hyperalgesia was evaluated 30 min and 4 h later. Two-way repeated-measures ANOVA followed by Bonferroni post hoc test showed no difference between the groups in PGE2-induced mechanical hyperalgesia (F(1,8) = 1.04; p > 0.05, when comparing both groups; NS, p = 0.3658), indicating that the proteasome system does not play a role in the prolongation of the hyperalgesia induced by PGE2 observed in type II priming. n = 6 paws per group.
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