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Abstract
BackgroundThe 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 natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein3 (NLRP3) inflammasome in microglia.MethodsCD-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.ResultsCo-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-1β 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-κB (NF-κB), and suppressed the level of reactive oxygen species in microglia.ConclusionsProcyanidins suppresses morphine-induced activation of NLRP3 inflammasome and inflammatory responses in microglia, and thus resulting in significant attenuation of morphine antinociceptive tolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0520-z) contains supplementary material, which is available to authorized users.
Highlights
The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use
Systemic administration of procyanidins improved the morphine tolerance and suppressed morphine-induced microglial activation in the spinal cord Some experiments were performed to investigate the role of procyanidins on morphine-induced tolerance in vivo
In summary, procyanidins could extend acute morphine analgesia and attenuate chronic morphine tolerance with a possible biological mechanism of inhibiting neuroinflammation represented by microglia activation
Summary
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. Our present study investigated the effects and possible mechanism of a natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein (NLRP3) inflammasome in microglia. Long-term use of morphine leads to analgesic tolerance, which greatly reduces the utilization of this drug. The mechanism of morphine tolerance is complicated involving many aspects, such as receptors, ion channels and neural networks [1,2,3]. Most investigations focused morphine tolerance on neurons. Compelling evidences reported recently have shown that morphine tolerance is due to the activation of microglia [11,12,13]. Studies demonstrate that morphine binds to Toll-like receptor 4 (TLR4), leading to the initiation of
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