Microvesicles shed from microglia activated by the P2X7-p38 pathway are involved in neuropathic pain induced by spinal nerve ligation in rats

Abstract

Microglia are critical in the pathogenesis of neuropathic pain. In this study, we investigated the role of microvesicles (MVs) in neuropathic pain induced by spinal nerve ligation (SNL) in rats. First, we found that MVs shed from microglia were increased in the cerebrospinal fluid and dorsal horn of the spinal cord after SNL. Next, MVs significantly reduced paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). In addition, the P2X7-p38 pathway was related to the bleb of MVs after SNL. Interleukin (IL)-1β was found to be significantly upregulated in the package of MVs, and PWT and PWL increased following inhibition with shRNA-IL-1β. Finally, the amplitude and frequency of spontaneous excitatory postsynaptic currents increased following stimulation with MVs. Our results indicate that the P2X7-p38 pathway is closely correlated with the shedding of MVs from microglia in neuropathic pain, and MVs had a significant effect on neuropathic pain by participating in the interaction between microglia and neurons.

Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats

“…These data imply that MV-like particles are released during the processes of microglial morphological change. Increasing data has shown that purinoceptors are involved in the morphological changes of microglia [21,27,51] and MV shedding [13,[47][48][49]. Persistently high ATP release was also detected in the peritraumatic region during the early stage of 2-6 h and returned to the background level 24 h after spinal cord injury [8].…”

“…Our previous data and other researchers have shown that high concentrations of extracellular ATP can stimulate microglial cells or macrophages to shed MVs [47][48][49]. MVs belong to the group of extracellular vesicles (EVs).…”

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

“…Neutral Sphingomyelinase Inhibition Alleviates Neuroinflammation decline in the IL-1b induced EVs in vitro and in vivo (Dickens et al, 2017). The ATP receptor P2X7 and its agonists have been implicated in the shedding of IL-1bcontaining MP (Bianco et al, 2009;Li et al, 2017) and release of proinflammatory mediators during CNS inflammatory events (Hide et al, 2000;Shieh et al, 2014), and these mechanisms require acid sphingomyelinase (Bianco et al, 2009). Here we examine the effect on nSMase inhibition on microglial pro-inflammatory responses and how it relates to microglial-mediated MP release.…”

P2X receptor channels in chronic pain pathways

“…Similarly, IL‐1β concentrations in serum were significantly elevated only in patients with neuropathic pain. While direct release of mature soluble IL‐1β is generally thought to be the main pathway for microglia‐to‐neuron communication, recent reports show that IL‐1β could also be packaged within microvesicles budding from microglia (Li et al ., ). Following spinal nerve ligation in rats, microglial microvesicles were detected in the CSF, and the associated pain symptoms could be alleviated with shRNA targeted against IL‐1β.…”