Peripheral Inflammatory Hyperalgesia Depends on P2X7 Receptors in Satellite Glial Cells

Abstract

Peripheral inflammatory hyperalgesia depends on the sensitization of primary nociceptive neurons. Inflammation drives molecular alterations not only locally but also in the dorsal root ganglion (DRG) where interleukin-1 beta (IL-1β) and purinoceptors are upregulated. Activation of the P2X7 purinoceptors by ATP is essential for IL-1β maturation and release. At the DRG, P2X7R are expressed by satellite glial cells (SGCs) surrounding sensory neurons soma. Although SGCs have no projections outside the sensory ganglia these cells affect pain signaling through intercellular communication. Therefore, here we investigated whether activation of P2X7R by ATP and the subsequent release of IL-1β in DRG participate in peripheral inflammatory hyperalgesia. Immunofluorescent images confirmed the expression of P2X7R and IL-1β in SGCs of the DRG. The function of P2X7R was then verified using a selective antagonist, A-740003, or antisense for P2X7R administered in the L5-DRG. Inflammation was induced by CFA, carrageenan, IL-1β, or PGE 2 administered in rat's hind paw. Blockage of P2X7R at the DRG reduced the mechanical hyperalgesia induced by CFA, and prevented the mechanical hyperalgesia induced by carrageenan or IL-1β, but not PGE 2. It was also found an increase in P2X7 mRNA expression at the DRG after peripheral inflammation. IL-1β production was also increased by inflammatory stimuli in vivo and in vitro, using SGC-enriched cultures stimulated with LPS. In LPS-stimulated cultures, activation of P2X7R by BzATP induced the release of IL-1β, which was blocked by A-740003. In summary, our data suggest that peripheral inflammation leads to the activation of P2X7R expressed by SGCs at the DRG. Then, ATP-induced activation of P2X7R mediates the release of IL-1β from SGC. This evidence places the SGC as an active player in the establishment of peripheral inflammatory hyperalgesia and highlights the importance of the events in DRG for the treatment of inflammatory diseases.

P2X7R-mediated Autophagic Impairment Contributes to Central Sensitization in a chronic Migraine Model with Recurrent Nitroglycerin Stimulation in Mice

“…A large number of studies have suggested that the up-regulation of P2 × 7R is involved in the cancer and neuropathic pain [25,[84][85][86][87][88]. Here, we reported increase in the expression of microglial P2 × 7R in the TNC area and con rmed the relationship between P2 × 7R and CM.…”

NETs Lead to Sympathetic Hyperactivity After Traumatic Brain Injury Through the LL37-Hippo/MST1 Pathway

“…Inhibition of NETosis by YW3-56 can reduce the expression of MST1, YAP and the release of IL-1β by microglia, indicating that NETs contribute to the activation of microglia and IL-1β secretion in the PVN. A previous study also found that activation of the P2 × 7 purinoceptors in the glial cell is essential for IL-1β release ( Neves et al, 2020 ). Besides, Zhao et al (2016) found that the Hippo/MSTI signaling pathway can regulate microglial activation.…”

Running wheel exercise induces therapeutic and preventive effects on inflammatory stimulus-induced persistent hyperalgesia in mice

“…They also showed that exercise reversed nerve injury-induced BDNF upregulation and glial hyperactivity on dorsal root ganglion (DRG), which can also be used as background to explain the mechanism of the exercise-induced analgesia showed in the present study. In this context, it is important to mention that DRG glial activation is required for the PGE 2 -induced hyperalgesia [ 43 , 44 ], which suggest that the analgesia induced by exercise observed in the present study could be mediated by a DRG glial mechanism.…”