Inhibition of Aquaporin-4 and its sub-cellular localization attenuates below-level central neuropathic pain via regulating astrocyte activation in a rat spinal cord injury model

The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the up-regulation of astrocytic Aquaporin-4 (AQP4) aggravated peripheral neuropathic pain after spinal nerve ligation in rats. Using a T13 spinal cord hemisection model, we showed that spinal AQP4 was markedly up-regulated after SCI and mainly expressed in astrocytes in the spinal dorsal horn (SDH). Inhibition of AQP4 with TGN020 suppressed astrocytes activation, attenuated the development and maintenance of below-level CNP and promoted motor function recovery in vivo. In primary astrocyte cultures, TGN020 also changed cell morphology, diminished cell proliferation and suppressed astrocyte activation. Moreover, T13 spinal cord hemisection induced cell-surface abundance of AQP4 channel and the perivascular localization in the SDH. Targeted inhibition of AQP4 sub-cellular localization with trifluoperazine effectively diminished astrocytes activation in vitro and further ablated astrocytes activation, attenuated the development and maintenance of below-level CNP, and accelerated functional recovery in vivo. Together, these results provide mechanistic insights into the roles of AQP4 in the development and maintenance of below-level CNP. Intervening with AQP4, including targeting AQP4 subcellular localization, might emerges as a promising agent to prevent chronic CNP after SCI.