CaMKII and CaV3.2 T-type calcium channel mediate Connexin-43-dependent inflammation by activating astrocytes in vincristine-induced neuropathic pain

Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, VCR therapy can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced pain (VINP) was accompanied by astrocyte activation; upregulation phospho-CaMKII (p-CaMKII), CaV3.2, and Connexin-43 (Cx43) expression; production release inflammatory cytokines chemokines in spinal cord. Similar situations were also observed cultures. Interestingly, these alterations all reversed intrathecal injection KN-93 (a CaMKII inhibitor) or l-Ascorbic acid CaV3.2 inhibitor). In addition, inhibited increase [Ca2+]i associated with activation. We verified knocking down inhibiting Cx43 level via siRNA Gap27 mimetic peptide) relieved hypersensitivity reduced factors; however, they did not affect activation p-CaMKII expression. Besides, overexpression through transfection plasmid expressions vitro. Therefore, may activate astrocytes increasing [Ca2+]i, thereby mediating Cx43-dependent inflammation VINP. Moreover, demonstrated signalling pathway involved inflammation, apoptosis, mitochondrial damage. Collectively, our findings show novel mechanism mediate activating induced VCR.