Astrocytic purinergic signalling contributes to the development and maintenance of neuropathic pain via modulation of glutamate release,Journal of Neurochemistry

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Astrocytic purinergic signalling contributes to the development and maintenance of neuropathic pain via modulation of glutamate release
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2023-03-04 , DOI: 10.1111/jnc.15800
Suting Liu ₁ , Hao Cheng ₁ , Liying Cui ₁ , Li Jin ₁ , Yunzi Li ₂ , Chao Zhu ₃ , Qing Ji ₁ , Jun Tang ₁

Affiliation

Although activation of astrocytes is critical in developing neuropathic pain (NP) following nerve injury, the underlying mechanisms of NP and therapeutic management for NP are still vague. Importantly, the decreases in the levels of astrocytic glutamate transporter-1 (GLT-1) in the spinal dorsal horn result in enhanced excitatory transmission and cause persistent pain. P2Y1 purinergic receptor (P2Y1R) has been shown to enhance many inflammatory processes. The up-regulated expression of astrocytic P2Y1R is crucial to participate in pain transduction under conditions of nerve injury and peripheral inflammation considering that P2Y1R is potentially involved in glutamate release and synaptic transmission. This study indicates that the expression of P2Y1R in the spinal cord was increased accompanied by the activation of A1 phenotype astrocytes in the rat model of spinal nerve ligation (SNL). Astrocyte-specific knockdown of P2Y1R alleviated SNL-induced nociceptive responses and mitigated A1 reactive astrocytes, which subsequently increased GLT-1 expression. Conversely, in naïve rats, P2Y1R over-expression induced a canonical NP-like phenotype and spontaneous hypernociceptive responses and increased the concentration of glutamate in the spinal dorsal horn. Besides, our in vitro data showed that the proinflammatory cytokine tumour necrosis factor-alpha contributes to A1/A2 astrocyte reactivity and Ca²⁺-dependent release of glutamate. Conclusively, our results provide novel insights that as a significant regulator of astrocytic A1/A2 polarization and neuroinflammation, P2Y1R may represent a potential target for the treatment of SNL-induced NP.

中文翻译：

星形胶质细胞嘌呤能信号通过调节谷氨酸释放促进神经性疼痛的发展和维持

尽管星形胶质细胞的激活对于神经损伤后神经性疼痛 (NP) 的发展至关重要，但 NP 的潜在机制和 NP 的治疗管理仍不明确。重要的是，脊髓背角星形胶质细胞谷氨酸转运体 1 (GLT-1) 水平的降低导致兴奋性传递增强并导致持续性疼痛。P2Y1 嘌呤能受体 (P2Y1R) 已显示可增强许多炎症过程。考虑到 P2Y1R 可能参与谷氨酸释放和突触传递，星形胶质细胞 P2Y1R 的上调表达对于在神经损伤和外周炎症条件下参与疼痛转导至关重要。本研究表明，在脊神经结扎（SNL）大鼠模型中，随着 A1 表型星形胶质细胞的激活，P2Y1R 在脊髓中的表达增加。P2Y1R 的星形胶质细胞特异性敲低减轻了 SNL 诱导的伤害性反应并减轻了 A1 反应性星形胶质细胞，随后增加了 GLT-1 的表达。相反，在幼稚大鼠中，P2Y1R 过度表达诱导了典型的 NP 样表型和自发的过度伤害反应，并增加了脊髓背角中谷氨酸的浓度。此外，我们的体外数据显示促炎细胞因子肿瘤坏死因子-α 有助于 A1/A2 星形胶质细胞反应性和 Ca P2Y1R 的星形胶质细胞特异性敲低减轻了 SNL 诱导的伤害性反应并减轻了 A1 反应性星形胶质细胞，随后增加了 GLT-1 的表达。相反，在幼稚大鼠中，P2Y1R 过度表达诱导了典型的 NP 样表型和自发的过度伤害反应，并增加了脊髓背角中谷氨酸的浓度。此外，我们的体外数据显示促炎细胞因子肿瘤坏死因子-α 有助于 A1/A2 星形胶质细胞反应性和 Ca P2Y1R 的星形胶质细胞特异性敲低减轻了 SNL 诱导的伤害性反应并减轻了 A1 反应性星形胶质细胞，随后增加了 GLT-1 的表达。相反，在幼稚大鼠中，P2Y1R 过度表达诱导了典型的 NP 样表型和自发的过度伤害反应，并增加了脊髓背角中谷氨酸的浓度。此外，我们的体外数据显示促炎细胞因子肿瘤坏死因子-α 有助于 A1/A2 星形胶质细胞反应性和 Ca²⁺ -依赖性谷氨酸释放。最后，我们的结果提供了新的见解，即作为星形胶质细胞 A1/A2 极化和神经炎症的重要调节剂，P2Y1R 可能代表治疗 SNL 诱导的 NP 的潜在靶点。

更新日期：2023-03-04

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