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抑制磷酸化钙/钙调蛋白依赖性蛋白激酶 IIα 通过调节背根神经节中的 P2X3 受体缓解链脲佐菌素诱导的糖尿病神经病理性疼痛。

Inhibition of phosphorylated calcium/calmodulin-dependent protein kinase IIα relieves streptozotocin-induced diabetic neuropathic pain through regulation of P2X3 receptor in dorsal root ganglia.

机构信息

Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China.

Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China.

出版信息

Purinergic Signal. 2023 Mar;19(1):99-111. doi: 10.1007/s11302-021-09829-z. Epub 2022 Jan 1.

DOI:10.1007/s11302-021-09829-z
PMID:34973115
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9984656/
Abstract

Diabetic neuropathic pain (DNP) is frequent among patients with diabetes. We previously showed that P2X3 upregulation in dorsal root ganglia (DRG) plays a role in streptozotocin (STZ)-induced DNP but the underlying mechanism is unclear. Here, a rat model of DNP was established by a single injection of STZ (65 mg/kg). Fasting blood glucose was significantly elevated from the 1 to 3 week. Paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) in diabetic rats significantly reduced from the 2 to 3 week. Western blot analysis revealed that elevated p-CaMKIIα levels in the DRG of DNP rats were accompanied by pain-associated behaviors while CaMKIIα levels were unchanged. Immunofluorescence revealed significant increase in the proportion of p-CaMKIIα immune positive DRG neurons (stained with NeuN) in the 2 and 3 week and p-CaMKIIα was co-expressed with P2X3 in DNP rats. KN93, a CaMKII antagonist, significantly reduce mechanical hyperalgesia and thermal hyperalgesia and these effects varied dose-dependently, and suppressed p-CaMKIIα and P2X3 upregulation in the DRGs of DNP rats. These results revealed that the p-CaMKIIα upregulation in DRG is involved in DNP, which possibly mediated P2X3 upregulation, indicating CaMKIIα may be an effective pharmacological target for DNP management.

摘要

糖尿病性神经病理性疼痛（DNP）在糖尿病患者中很常见。我们之前的研究表明，背根神经节（DRG）中 P2X3 的上调在链脲佐菌素（STZ）诱导的 DNP 中起作用，但潜在机制尚不清楚。在这里，通过单次注射 STZ（65mg/kg）建立了 DNP 大鼠模型。糖尿病大鼠的空腹血糖从第 1 周到第 3 周显著升高。糖尿病大鼠的足底撤回阈值（PWT）和足底撤回潜伏期（PWL）从第 2 周到第 3 周显著降低。Western blot 分析显示，DNP 大鼠 DRG 中升高的 p-CaMKIIα 水平伴随着疼痛相关行为，而 CaMKIIα 水平不变。免疫荧光显示，在第 2 周和第 3 周，p-CaMKIIα 免疫阳性 DRG 神经元（用 NeuN 染色）的比例显著增加，p-CaMKIIα 在 DNP 大鼠中与 P2X3 共表达。CaMKII 拮抗剂 KN93 显著减轻机械性痛觉过敏和热痛觉过敏，这些作用呈剂量依赖性变化，并抑制 DNP 大鼠 DRG 中 p-CaMKIIα 和 P2X3 的上调。这些结果表明，DRG 中 p-CaMKIIα 的上调参与了 DNP，其可能介导了 P2X3 的上调，表明 CaMKIIα 可能是 DNP 管理的有效药物靶点。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fb5/9984656/e0cab9f3ed66/11302_2021_9829_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fb5/9984656/755b94d80fed/11302_2021_9829_Fig7_HTML.jpg
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