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 PGE2 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 PGE2. 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.
Highlights
In the nociceptive system, primary afferent neurons transduce the injury information at its peripheral endings and transmit the resulting signal to the central nervous system (CNS)
A-740003 (0.1 mM/5 μL) administered in the ipsilateral L5 dorsal root ganglion (DRG) immediately before the inflammatory stimuli prevented the hyperalgesia induced by carrageenan and IL-1β (Figures 1B,C; Unpaired t-test; t = 23.35 and t = 5.89 respectively, P < 0.001, n = 6), but did not affect the hyperalgesia induced by prostaglandin E2 (PGE2) (Figure 1D; Unpaired Student’s t-test; t = 0.23, P = 0.816, n = 6)
Satellite glial cells (SGCs) have no projections outside the sensory ganglia, in this study, we detected a major process occurring at the dorsal root ganglion (DRG) involving the active participation of satellite glial cells (SGCs) in the development of peripheral inflammatory hyperalgesia
Summary
Primary afferent neurons transduce the injury information at its peripheral endings and transmit the resulting signal to the central nervous system (CNS). A layer of satellite glial cells (SGCs) tightly wrap each neuronal soma, which in turn is enclosed by connective tissue to create a physically isolated unit (Devor, 1999; Hanani, 2005; Pannese, 2010; Esposito et al, 2019) This singular structure suggests active participation of SGCs in the processing of sensory information by communicating with neurons (Hanani, 2005; Costa and Moreira Neto, 2015; Fan et al, 2019). After peripheral tissue injury or inflammation, molecular alterations in the DRG are involved in the development of hyperexcitability of nociceptive neurons (Krames, 2014; Berta et al, 2017) Examples of those alterations include the upregulation of P2X receptors (Kushnir et al, 2011) and upregulation of the proinflammatory cytokine interleukin-1β (IL-1β) (Guo et al, 2007; Araldi et al, 2013). In this study, we hypothesized that ATP-induced activation of P2X7R and the subsequent release of IL-1β by SGCs could be a major process in the DRG for the establishment of inflammatory hyperalgesia in the peripheral tissue
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