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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 possible influence of minocycline on analgesia after opioid receptors ligands.In our opinion, activated spinal microglia are key factors in the development of neuropathic pain and play a major role in the antagonizing of some opioids effectiveness. The results of our paper show for the first time that that DOR, in contrast to MOR and KOR, is not present in microglial cells. This phenomenon might be responsible for the different analgesic effects of MOR, KOR and DOR ligands (Fig. 2 and 3). We provide evidence that minocycline (a potent inhibitor of microglial activation and proliferation) enhances the effects of selective MOR (DAMGO; Fig. 2C,D) and selective KOR (U50,488H; Fig. 2E,F) agonists by inhibition of microglial cell activation. The effectiveness of DOR agonists (DPDPE, deltorphin II and SNC80) is not changed by minocycline (Fig. 3A–F). Our results indicate that an important element of the effectiveness of opioid drugs in neuropathic pain is the activation of microglia. The lack of DOR receptors in these cells causes that DOR receptor-mediated analgesia is not weaker under neuropathic pain, in which there is a strong activation of microglia. Earlier inhibition of microglial activation by minocycline administration therefore did not influence the effect of DOR selective agonists. The above results indicate not only that minocycline potentiates analgesia after MOR and KOR agonists but also that DOR is a potentially important target in the search for new drugs that would be effective against neuropathic pain.
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pone-0104420-g006: The possible influence of minocycline on analgesia after opioid receptors ligands.In our opinion, activated spinal microglia are key factors in the development of neuropathic pain and play a major role in the antagonizing of some opioids effectiveness. The results of our paper show for the first time that that DOR, in contrast to MOR and KOR, is not present in microglial cells. This phenomenon might be responsible for the different analgesic effects of MOR, KOR and DOR ligands (Fig. 2 and 3). We provide evidence that minocycline (a potent inhibitor of microglial activation and proliferation) enhances the effects of selective MOR (DAMGO; Fig. 2C,D) and selective KOR (U50,488H; Fig. 2E,F) agonists by inhibition of microglial cell activation. The effectiveness of DOR agonists (DPDPE, deltorphin II and SNC80) is not changed by minocycline (Fig. 3A–F). Our results indicate that an important element of the effectiveness of opioid drugs in neuropathic pain is the activation of microglia. The lack of DOR receptors in these cells causes that DOR receptor-mediated analgesia is not weaker under neuropathic pain, in which there is a strong activation of microglia. Earlier inhibition of microglial activation by minocycline administration therefore did not influence the effect of DOR selective agonists. The above results indicate not only that minocycline potentiates analgesia after MOR and KOR agonists but also that DOR is a potentially important target in the search for new drugs that would be effective against neuropathic pain.

Mentions: The results of the present study document for the first time that DOR, in contrast to MOR and KOR, are not present in microglial cells (Figure 6). In conclusion, we provide evidence that minocycline not only diminishes neuropathic pain-related behaviour but also enhances the effectiveness of morphine and selective MOR and KOR opioid ligands under neuropathic pain conditions. Our findings lend support to the view that neuroimmunological changes in the spinal cord and DRG are important for opioid effectiveness in neuropathic pain. In our opinion, activated spinal microglia are key factors in not only the development of neuropathic pain but also in the different efficacies of opioid analgesics. Our results also suggest that DOR analgesia is not dependent on injury-induced microglial activation. We therefore suggest that DOR is an interesting target for the development of new drugs that would be effective against neuropathic pain.


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 possible influence of minocycline on analgesia after opioid receptors ligands.In our opinion, activated spinal microglia are key factors in the development of neuropathic pain and play a major role in the antagonizing of some opioids effectiveness. The results of our paper show for the first time that that DOR, in contrast to MOR and KOR, is not present in microglial cells. This phenomenon might be responsible for the different analgesic effects of MOR, KOR and DOR ligands (Fig. 2 and 3). We provide evidence that minocycline (a potent inhibitor of microglial activation and proliferation) enhances the effects of selective MOR (DAMGO; Fig. 2C,D) and selective KOR (U50,488H; Fig. 2E,F) agonists by inhibition of microglial cell activation. The effectiveness of DOR agonists (DPDPE, deltorphin II and SNC80) is not changed by minocycline (Fig. 3A–F). Our results indicate that an important element of the effectiveness of opioid drugs in neuropathic pain is the activation of microglia. The lack of DOR receptors in these cells causes that DOR receptor-mediated analgesia is not weaker under neuropathic pain, in which there is a strong activation of microglia. Earlier inhibition of microglial activation by minocycline administration therefore did not influence the effect of DOR selective agonists. The above results indicate not only that minocycline potentiates analgesia after MOR and KOR agonists but also that DOR is a potentially important target in the search for new drugs that would be effective against neuropathic pain.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104420-g006: The possible influence of minocycline on analgesia after opioid receptors ligands.In our opinion, activated spinal microglia are key factors in the development of neuropathic pain and play a major role in the antagonizing of some opioids effectiveness. The results of our paper show for the first time that that DOR, in contrast to MOR and KOR, is not present in microglial cells. This phenomenon might be responsible for the different analgesic effects of MOR, KOR and DOR ligands (Fig. 2 and 3). We provide evidence that minocycline (a potent inhibitor of microglial activation and proliferation) enhances the effects of selective MOR (DAMGO; Fig. 2C,D) and selective KOR (U50,488H; Fig. 2E,F) agonists by inhibition of microglial cell activation. The effectiveness of DOR agonists (DPDPE, deltorphin II and SNC80) is not changed by minocycline (Fig. 3A–F). Our results indicate that an important element of the effectiveness of opioid drugs in neuropathic pain is the activation of microglia. The lack of DOR receptors in these cells causes that DOR receptor-mediated analgesia is not weaker under neuropathic pain, in which there is a strong activation of microglia. Earlier inhibition of microglial activation by minocycline administration therefore did not influence the effect of DOR selective agonists. The above results indicate not only that minocycline potentiates analgesia after MOR and KOR agonists but also that DOR is a potentially important target in the search for new drugs that would be effective against neuropathic pain.
Mentions: The results of the present study document for the first time that DOR, in contrast to MOR and KOR, are not present in microglial cells (Figure 6). In conclusion, we provide evidence that minocycline not only diminishes neuropathic pain-related behaviour but also enhances the effectiveness of morphine and selective MOR and KOR opioid ligands under neuropathic pain conditions. Our findings lend support to the view that neuroimmunological changes in the spinal cord and DRG are important for opioid effectiveness in neuropathic pain. In our opinion, activated spinal microglia are key factors in not only the development of neuropathic pain but also in the different efficacies of opioid analgesics. Our results also suggest that DOR analgesia is not dependent on injury-induced microglial activation. We therefore suggest that DOR is an interesting target for the development of new drugs that would be effective against neuropathic pain.

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