Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia

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.

Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice

“…We detected an increase in arginase-1/Iba-1 double immunopositive cells in 5 weeks old db/db mice compared to age-matched db/+ controls, suggesting that this microglia displayed a M2 anti-inflammatory phenotype at an early stage of DR. However, during DR progression in db/db mice (8 weeks), microglia lose arginase-1 immunostaining and this concurs with the detection of active caspase-1, a key component of the inflammasome that has been involved in the neuroinflammatory responses of microglia [48,49]. This result suggests that the involvement of the inflammasome system at this stage of DR, monitored by the activation of caspase-1, is likely related to the polarization switch of microglia towards M1.…”

Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy

“…Excessive levels of ROS are also associated with decreases in cognitive performance. The ability of morphine to elicit alterations in ROS levels is consistent with data from other cells such as murine macrophages and microglia (Bhat et al, 2004;Cai et al, 2016b).…”

Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression

“…Studies also showed that the consumption of procyanidin-rich foods can lower the incidence of inflammatory diseases, including metabolic syndrome and atherosclerosis [19]. Moreover, we have previously reported that procyanidins can strongly inhibit the morphine-induced activation of NLRP3 inflammasomes in microglia [20]. On that basis, we hypothesized that procyanidins, a safe and effective natural product, might attenuate gout pain by inhibiting NLRP3 inflammasome activation and IL-1β maturation in macrophages.…”