Abstract
Activation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.
Highlights
Peripheral nerve injury often results in neuropathic pain, which persists even after the initial injury heals
The current study demonstrates that microglial Hv1 proton channels contributed to reactive oxygen species (ROS) generation, astrocyte activation, IFN-γ production, and the subsequent neuropathic pain following peripheral nerve injury (Fig. 8)
These results provide novel insights into Hv1 function in microglia-astrocyte interaction and the pathogenesis of neuropathic pain
Summary
Peripheral nerve injury often results in neuropathic pain, which persists even after the initial injury heals. Such hypersensitivities are typically manifest as increased sensitivity to normally painful (hyperalgesia) and normally. Peripheral nerve injuries reliably induce microglial activation, which is indicated by hypertrophic morphologies, proliferation, Peng et al Mol Brain (2021) 14:99 gene expression alterations, and release of cytokines/ chemokines [3, 10]. Peripheral nerve injuries induce spinal astrocyte activation with increased glial fibrillary acidic protein (GFAP) expression. The release of pro-inflammatory cytokines/chemokines from activated spinal astrocytes, such as IFN-γ, MCP-1, and CXCL1, is able to prolong hypersensitive pain state after peripheral nerve injuries [24]
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