Selective suppression of microglial activation by paeoniflorin attenuates morphine tolerance.
Eur J Pain. 2015 Aug ;19(7):908-19. Epub 2014 Nov 16. PMID: 25400125
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.
CONCLUSION: Paeoniflorin directly suppresses morphine-induced microglial activation and thus results in potentiation of morphine acute analgesia and attenuation of morphine chronic antinociceptive tolerance.