Selective suppression of microglial activation by paeoniflorin attenuates morphine tolerance.

Abstract

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. 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. (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. Paeoniflorin directly suppresses morphine-induced microglial activation and thus results in potentiation of morphine acute analgesia and attenuation of morphine chronic antinociceptive tolerance.