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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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Mentions: The chemicals used in this study and their sources were as follows: morphine hydrochloride – Polfa (Kutno, Poland); DAMGO (Sigma-Aldrich, USA), Deltorphin II (Sigma-Aldrich, USA), DPDPE (Sigma-Aldrich, USA), U50,488H (Tocris, UK), SNC80 (Sigma-Aldrich, USA) and minocycline hydrochloride (Sigma-Aldrich, USA). Minocycline (MC; 30 mg/kg; i.p.) was dissolved in sterile water and pre-emptively administered intraperitoneally 16 h and 1 h before CCI and then twice daily for 7 days. This method of minocycline administration was used throughout the work and is referred to in the text as “repeated administration”. The control groups received a vehicle (water for injection) according to the same schedule. One hour after the last morning of minocycline or vehicle administration on day 7 after CCI, morphine (M; 20; 40 µg; 62.3 nM; 124.6 nM), DAMGO (MOR selective ligand; 1; 2 µg; 1.94 nM; 3.9 nM), U50,488H (KOR selective ligand; 25; 50 µg; 61.6 nM; 123.2 nM), DPDPE (DOR I selective ligand; 10; 20 µg; 15.48 nM; 30.96 nM), deltorphin II (del II; DOR II selective ligand; 1.5; 15 µg; 1.9 nM; 19 nM), SNC80 (10; 20 µg; 22.24 nM; 44.48 nM) or a vehicle was intrathecally injected. The von Frey test (25 and 45 min later) and cold plate tests (30 and 50 min later) were carried out after vehicle or opioid agonist administration (Figure 1).


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)

Drug administration.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104420-g001: Drug administration.
Mentions: The chemicals used in this study and their sources were as follows: morphine hydrochloride – Polfa (Kutno, Poland); DAMGO (Sigma-Aldrich, USA), Deltorphin II (Sigma-Aldrich, USA), DPDPE (Sigma-Aldrich, USA), U50,488H (Tocris, UK), SNC80 (Sigma-Aldrich, USA) and minocycline hydrochloride (Sigma-Aldrich, USA). Minocycline (MC; 30 mg/kg; i.p.) was dissolved in sterile water and pre-emptively administered intraperitoneally 16 h and 1 h before CCI and then twice daily for 7 days. This method of minocycline administration was used throughout the work and is referred to in the text as “repeated administration”. The control groups received a vehicle (water for injection) according to the same schedule. One hour after the last morning of minocycline or vehicle administration on day 7 after CCI, morphine (M; 20; 40 µg; 62.3 nM; 124.6 nM), DAMGO (MOR selective ligand; 1; 2 µg; 1.94 nM; 3.9 nM), U50,488H (KOR selective ligand; 25; 50 µg; 61.6 nM; 123.2 nM), DPDPE (DOR I selective ligand; 10; 20 µg; 15.48 nM; 30.96 nM), deltorphin II (del II; DOR II selective ligand; 1.5; 15 µg; 1.9 nM; 19 nM), SNC80 (10; 20 µg; 22.24 nM; 44.48 nM) or a vehicle was intrathecally injected. The von Frey test (25 and 45 min later) and cold plate tests (30 and 50 min later) were carried out after vehicle or opioid agonist administration (Figure 1).

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