Procyanidins Alleviates Morphine Tolerance By Inhibiting Activation Of NLRP3 Inflammasome In Microglia

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 plays a critical role in morphine tolerance.The inhibitor of microglia is effective to attenuate the tolerance;however,the mechanism is not fully understood.Our present study investigated the effects and possible mechanism of a natxural product procyanidins,in improving morphine tolerance via its specific inhibition on NLRP3 infdammasome in microglia.Methods:CD-1 mice were used for tail-flick test to evaluate the degree of pain.The microglial cell line BV-2 was used to investigate the effects and the mechanism of procyanidins.Reactive oxygen species(ROS)produced from BV-2 cells was evaluated by flow cytometry.Cell signaling was measured by western blot assay and immunofluorescence assay.Results:Co-administration of procyanidins with morphine potentiated its antinociception effect and attenuated the development of acute and chronic morphine tolerance.Procyanidins also inhibited morphine-induced increase of interleukin-1?and activation of NOD-like receptor protein3(NLRP3)inflammasome.Furthermore,procyanidins decreased the phosphorylation of p38 mitogen-activated protein kinase,inhibited the translocation of nuclear factor-?B(NF-?B)and suppressed the level of reactive oxygen species in microglia.Conclusion:Procyanidins suppresses morphine-induced activation of NLRP3 inflamasome and inflammatory responses in microglia,and thus resulting in significant attenuation of-morphine antinociceptive tolerance.