Selective suppression of microglial activation by paeoniflorin attenuates morphine tolerance.
BACKGROUND
The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of a natural compound, paeoniflorin, in morphine tolerance via its specific inhibition of microglial activation.


METHODS
The microglia cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. Nociception was assessed in Sprague-Dawley rats and CD-1 mice using Hargreaves' methods or the hot-plate test, respectively.


RESULTS
(1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase (MAPK) phosphorylation, nuclear factor (NF)-κB translocation and proinflammatory cytokine expression. These changes are inhibited by paeoniflorin. (2) Co-administration of paeoniflorin with morphine potentiates morphine antinociception by inhibiting p38 MAPK/NF-κB signalling in the spinal cord. (3) Co-administration of paeoniflorin suppresses morphine-increased expression of toll-like receptor-4 both in BV-2 cells and within the spinal cord following chronic morphine treatment.


CONCLUSIONS
Paeoniflorin directly suppresses morphine-induced microglial activation and thus results in potentiation of morphine acute analgesia and attenuation of morphine chronic antinociceptive tolerance.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, China.|Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
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Jiang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, China.|Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
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Xu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, China.|Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
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Chen
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, China.|Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, China.
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Han
Department of Physiology, Nanjing University of Traditional Chinese Medicine, China.
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Tang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, China.
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Yang
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
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Zhang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, China.
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Liu
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004357:Drug Synergism; D004361:Drug Tolerance; D005260:Female; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D039821:Monoterpenes / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D006027:Glycosides
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D005960:Glucosides; D039821:Monoterpenes; D009020:Morphine; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; C015423:peoniflorin; D006027:Glycosides