Mirror image pain mediated by D2 receptor regulation of astrocytic Cx43 phosphorylation and channel opening.

Qinghu Yang, Ming Jiang, Sen Xu, Liang Yang, Pan Yang, Yutian Song, Hongni Zhu, Yu Wang, Yahan Sun, Chengxiang Yan, Zhaoyue Yuan, Xia Liu, Zhantao Bai

Biochimica et biophysica acta. Molecular basis of disease 2023 Apr

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Mirror image pain (MIP), a clinical syndrome of contralateral pain hypersensitivity caused by unilateral injury, has been identified in various neuropathological conditions. Gap junctional protein Connexin 43 (Cx43), its phosphorylation levels and dopamine D2 receptor (DRD2) play key integrating roles in pain processing. We presume D2DR activity may affect Cx43 hemichannel opening via Cx43 phosphorylation levels to regulate MIP. This study shows that spinal astrocytic Cx43 directly interacts with DRD2 to mediate MIP. DRD2 and Cx43 expression levels were asymmetrically elevated in bilateral spinal during MIP, and DRD2 modulated the opening of primary astrocytic Cx43 hemichannels. Furthermore, Cx43 phosphorylation at Ser373 was increased during MIP, but decreased in DRD2 knockout (KO) mice. Finally, activation of spinal protein kinase A (PKA) altered the expression of Cx43 and its phosphorylation bilaterally, thus reversing the analgesic effect in DRD2 KO mice. Together, these data reveal that spinal Cx43 phosphorylation and channel opening are regulated by DRD2 via PKA activation, and that spinal Cx43 and DRD2 are key molecular sensors mediating mirror image pain. Copyright © 2023. Published by Elsevier B.V.

Citation

Qinghu Yang, Ming Jiang, Sen Xu, Liang Yang, Pan Yang, Yutian Song, Hongni Zhu, Yu Wang, Yahan Sun, Chengxiang Yan, Zhaoyue Yuan, Xia Liu, Zhantao Bai. Mirror image pain mediated by D2 receptor regulation of astrocytic Cx43 phosphorylation and channel opening. Biochimica et biophysica acta. Molecular basis of disease. 2023 Apr;1869(4):166657