Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses

Abstract

Background Neuropathic pain is still a challenge for clinical treatment as a result of the comprehensive pathogenesis. Although emerging evidence demonstrates the pivotal role of glial cells in regulating neuropathic pain, the role of Schwann cells and their underlying mechanisms still need to be uncovered. Pannexin 1 (Panx 1), an important membrane channel for the release of ATP and inflammatory cytokines, as well as its activation in central glial cells, contributes to pain development. Here, we hypothesized that Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain. Methods A mouse model of chronic constriction injury (CCI) in CD1 adult mice or P0-Cre transgenic mice, and in vitro cultured Schwann cells were used. Intrasciatic injection with Panx 1 blockers or the desired virus was used to knock down the expression of Panx 1. Mechanical and thermal sensitivity was assessed using Von Frey and a hot plate assay. The expression of Panx 1 was measured using qPCR, western blotting, and immunofluorescence. The production of cytokines was monitored through qPCR and enzyme-linked immunosorbent assay (ELISA). Panx1 channel activity was detected by ethidium bromide (EB) uptake. Results CCI induced persistent neuroinflammatory responses and upregulation of Panx 1 in Schwann cells. Intrasciatic injection of Panx 1 blockers, carbenoxolone (CBX), probenecid, and Panx 1 mimetic peptide (10Panx) effectively reduced mechanical and heat hyperalgesia. Probenecid treatment of CCI-induced mice significantly reduced Panx 1 expression in Schwann cells, but not in dorsal root ganglion (DRG). In addition, Panx 1 knockdown in Schwann cells with Panx 1 shRNA-AAV in P0-Cre mice significantly reduced CCI-induced neuropathic pain. To determine whether Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain, we evaluated its effect in LPS-treated Schwann cells. We found that inhibition of Panx 1 via CBX and Panx 1-siRNA effectively attenuated the production of selective cytokines, as well as its mechanism of action being dependent on both Panx 1 channel activity and its expression. Conclusion In this study, we found that CCI-related neuroinflammation correlates with Panx 1 activation in Schwann cells, indicating that inhibition of Panx 1 channels in Schwann cells reduces neuropathic pain through the suppression of neuroinflammatory responses.

Salidroside alleviates inflammatory reaction and sciatic nerve injury by inhibiting AKT/NF-κB pathway

“…When PNI occurs, the distal nerve bers show Wallerian degeneration, and Schwann cells proliferate and aggregate to the endocardium. Multiple cytokines and growth factors interact with axons, participate in various stages of peripheral nerve injury repair and regeneration, and play an important role in the quality and speed of nerve regeneration [15,16] . Through pathological examination of sciatic nerve in rats, we also found that after sciatic nerve injury, the protective effect of myelin sheath was disrupted, axons showed vacuolar degeneration in different degrees, and in ammatory cells in ltrated obviously.…”

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

“…Panx 1, is an essential membrane channel for ATP and neurokine release, aside from its usual activation in central glial cells in pain generation and propagation (Penuela et al., 2013; Yang et al., 2019). Schwann cell Panx 1 plays a role in the synchronization of neuromediated inflammation and participates in neuropathic pain (Wang, Li, et al., 2022). Neuromediated inflammation correlates with pannexin 1 activation in Schwann cells, demonstrating that when Panx 1 channels are inhibited, it reduces neuropathic pain by arresting neuroinflammatory processes (Wang, Li, et al., 2022).…”

“…Schwann cell Panx 1 plays a role in the synchronization of neuromediated inflammation and participates in neuropathic pain (Wang, Li, et al., 2022). Neuromediated inflammation correlates with pannexin 1 activation in Schwann cells, demonstrating that when Panx 1 channels are inhibited, it reduces neuropathic pain by arresting neuroinflammatory processes (Wang, Li, et al., 2022).…”

“…In neuropathic pain development, pannexin 1 activation occurs in the dorsal root ganglion, astrocytes, and microglia (Wang, Li, et al., 2022). In the cornea, pannexin 1 is decreased in stromal nerves as demonstrated in a mouse model (Cui et al., 2016; Rhodes et al., 2021).…”

“…In corneal neuropathic pain, there is a progression from acute to chronic pain; however, the underlying mechanism of this transition remains unclear. Recent studies have demonstrated that this transition is activated through persistent chronic inflammation via triggered glial cells (Skaper et al., 2013; Wang, Li, et al., 2022). These studies have shown that microglial depletion and astrocyte suppression through processes such as genetic ablation ameliorate neuropathic pain (Peng et al., 2021).…”