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Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain.

Mika J, Popiolek-Barczyk K, Rojewska E, Makuch W, Starowicz K, Przewlocka B - PLoS ONE (2014)

Bottom Line: Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI.Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions.In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

ABSTRACT
The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10-20 µg), DAMGO (1-2 µg) and U50,488H (25-50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg), deltorphin II (1.5-15 µg) and SNC80 (10-20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.

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The effects of morphine, DAMGO and U50,488H on vehicle- and minocycline-treated CCI-exposed rats.The response to morphine, DAMGO and U50,488H was measured 25 and 45(A, C, E) and 30 and 50 minutes after administration by the cold plate test (B, D, F). Minocycline (MC; 30 mg/kg; i.p.) was administered intraperitoneally pre-emptively 16 h and 1 h before CCI, and then repeatedly twice daily for 7 days. Vehicle-treated and minocycline-treated rats received intrathecal morphine (M; 20; 40 µg/5 µl), DAMGO (1; 2 µg/5 µl) or U50,488H (25; 50 µg/5 µl) one hour after the last morning administration on day 7 after CCI. The data are presented as the mean response ± S.E.M. (8–16 rats per group). The results of the experiments were statistically evaluated using One-way Analyses of Variance (ANOVA). The differences between the treatment groups throughout the study were further analysed with Bonferroni's post-hoc tests. *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences compared with vehicle-treated CCI-exposed rats; #P<0.05, ##P<0.01 and ###P<0.001 indicate significant differences between vehicle-treated CCI-exposed rats that received a single dose of morphine and minocycline-treated CCI-exposed rats that received a single dose of morphine, DAMGO or U50,488H. Dotted line is a value for naïve animals (for von Frey test 25.8 g; for cold plate test 29.7 s).
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pone-0104420-g002: The effects of morphine, DAMGO and U50,488H on vehicle- and minocycline-treated CCI-exposed rats.The response to morphine, DAMGO and U50,488H was measured 25 and 45(A, C, E) and 30 and 50 minutes after administration by the cold plate test (B, D, F). Minocycline (MC; 30 mg/kg; i.p.) was administered intraperitoneally pre-emptively 16 h and 1 h before CCI, and then repeatedly twice daily for 7 days. Vehicle-treated and minocycline-treated rats received intrathecal morphine (M; 20; 40 µg/5 µl), DAMGO (1; 2 µg/5 µl) or U50,488H (25; 50 µg/5 µl) one hour after the last morning administration on day 7 after CCI. The data are presented as the mean response ± S.E.M. (8–16 rats per group). The results of the experiments were statistically evaluated using One-way Analyses of Variance (ANOVA). The differences between the treatment groups throughout the study were further analysed with Bonferroni's post-hoc tests. *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences compared with vehicle-treated CCI-exposed rats; #P<0.05, ##P<0.01 and ###P<0.001 indicate significant differences between vehicle-treated CCI-exposed rats that received a single dose of morphine and minocycline-treated CCI-exposed rats that received a single dose of morphine, DAMGO or U50,488H. Dotted line is a value for naïve animals (for von Frey test 25.8 g; for cold plate test 29.7 s).

Mentions: All vehicle-treated CCI rats exhibited neuropathic pain symptoms in the behavioral tests. The rats exhibited strong allodynia on the seventh day after ligation as measured by the von Frey test (11.6 g±0.6 vs. 25.8 g±0.2 for naïve rats) (Fig. 2A,C,E; 3A,C,E) and potent hyperalgesia as measured by the cold plate test (7.6 s±0.9 vs. 29.7 s±0.3 for naïve rats) (Fig. 2B,D,F; 3B,D,F). Repeated administration of minocycline (MC; 30 mg/kg; i.p.) attenuated allodynia (17.4 g±0.5 vs. 11.6 g±0.6 for the vehicle-treated CCI rats) (Fig. 2A,C,E; 3A,C,E) and also hyperalgesia (12.1 s±0.9 vs. 7.6 s±0.9 for the vehicle-treated CCI rats) (Fig. 2B,D,F; 3B,D,F) to a similar extent at both time points.


Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain.

Mika J, Popiolek-Barczyk K, Rojewska E, Makuch W, Starowicz K, Przewlocka B - PLoS ONE (2014)

The effects of morphine, DAMGO and U50,488H on vehicle- and minocycline-treated CCI-exposed rats.The response to morphine, DAMGO and U50,488H was measured 25 and 45(A, C, E) and 30 and 50 minutes after administration by the cold plate test (B, D, F). Minocycline (MC; 30 mg/kg; i.p.) was administered intraperitoneally pre-emptively 16 h and 1 h before CCI, and then repeatedly twice daily for 7 days. Vehicle-treated and minocycline-treated rats received intrathecal morphine (M; 20; 40 µg/5 µl), DAMGO (1; 2 µg/5 µl) or U50,488H (25; 50 µg/5 µl) one hour after the last morning administration on day 7 after CCI. The data are presented as the mean response ± S.E.M. (8–16 rats per group). The results of the experiments were statistically evaluated using One-way Analyses of Variance (ANOVA). The differences between the treatment groups throughout the study were further analysed with Bonferroni's post-hoc tests. *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences compared with vehicle-treated CCI-exposed rats; #P<0.05, ##P<0.01 and ###P<0.001 indicate significant differences between vehicle-treated CCI-exposed rats that received a single dose of morphine and minocycline-treated CCI-exposed rats that received a single dose of morphine, DAMGO or U50,488H. Dotted line is a value for naïve animals (for von Frey test 25.8 g; for cold plate test 29.7 s).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4126741&req=5

pone-0104420-g002: The effects of morphine, DAMGO and U50,488H on vehicle- and minocycline-treated CCI-exposed rats.The response to morphine, DAMGO and U50,488H was measured 25 and 45(A, C, E) and 30 and 50 minutes after administration by the cold plate test (B, D, F). Minocycline (MC; 30 mg/kg; i.p.) was administered intraperitoneally pre-emptively 16 h and 1 h before CCI, and then repeatedly twice daily for 7 days. Vehicle-treated and minocycline-treated rats received intrathecal morphine (M; 20; 40 µg/5 µl), DAMGO (1; 2 µg/5 µl) or U50,488H (25; 50 µg/5 µl) one hour after the last morning administration on day 7 after CCI. The data are presented as the mean response ± S.E.M. (8–16 rats per group). The results of the experiments were statistically evaluated using One-way Analyses of Variance (ANOVA). The differences between the treatment groups throughout the study were further analysed with Bonferroni's post-hoc tests. *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences compared with vehicle-treated CCI-exposed rats; #P<0.05, ##P<0.01 and ###P<0.001 indicate significant differences between vehicle-treated CCI-exposed rats that received a single dose of morphine and minocycline-treated CCI-exposed rats that received a single dose of morphine, DAMGO or U50,488H. Dotted line is a value for naïve animals (for von Frey test 25.8 g; for cold plate test 29.7 s).
Mentions: All vehicle-treated CCI rats exhibited neuropathic pain symptoms in the behavioral tests. The rats exhibited strong allodynia on the seventh day after ligation as measured by the von Frey test (11.6 g±0.6 vs. 25.8 g±0.2 for naïve rats) (Fig. 2A,C,E; 3A,C,E) and potent hyperalgesia as measured by the cold plate test (7.6 s±0.9 vs. 29.7 s±0.3 for naïve rats) (Fig. 2B,D,F; 3B,D,F). Repeated administration of minocycline (MC; 30 mg/kg; i.p.) attenuated allodynia (17.4 g±0.5 vs. 11.6 g±0.6 for the vehicle-treated CCI rats) (Fig. 2A,C,E; 3A,C,E) and also hyperalgesia (12.1 s±0.9 vs. 7.6 s±0.9 for the vehicle-treated CCI rats) (Fig. 2B,D,F; 3B,D,F) to a similar extent at both time points.

Bottom Line: Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI.Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions.In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

ABSTRACT
The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10-20 µg), DAMGO (1-2 µg) and U50,488H (25-50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg), deltorphin II (1.5-15 µg) and SNC80 (10-20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.

Show MeSH
Related in: MedlinePlus