cAMP-PKA signaling is involved in regulation of spinal HCN channels function in diabetic neuropathic pain
cAMP-PKA signaling is involved in regulation of spinal HCN channels function in diabetic neuropathic pain
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DOI：
10.1016/j.neulet.2021.135763
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发表时间：
2021-02
影响因子：
2.5
通讯作者：
Yanqiao Ma;Ji Chen;Deqian Yu;B. Wei;H. Jin;Junwei Zeng;Xiaohong Liu
中科院分区：
文献类型：
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作者：
Yanqiao Ma;Ji Chen;Deqian Yu;B. Wei;H. Jin;Junwei Zeng;Xiaohong Liu
环磷酸腺苷-蛋白激酶A（cAMP-PKA）信号在超极化激活的环核苷酸门控（HCN）通道介导的神经病理性疼痛和炎性疼痛中起关键作用。然而，没有证据表明cAMP PKA信号通路参与了脊髓HCN通道功能在糖尿病神经病理性疼痛（DNP）发生中的调节。本研究旨在阐明HCN通道对链脲佐菌素诱导的糖尿病大鼠模型神经病理性疼痛的影响，以及cAMP PKA信号转导是否参与HCN通道功能的调节。本文观察了鞘内注射HCN通道阻断剂ZD 7288、cAMP抑制剂SQ 22536和PKA抑制剂H-89对DNP大鼠伤害性行为的影响。测定大鼠机械性缩痛阈值（MWT）评价大鼠的疼痛行为。测定大鼠脊髓背角HCN 2、HCN 4通道和PKA蛋白表达水平。并对大鼠脊髓背角cAMP含量进行分析。我们发现DNP大鼠表现出显著的机械性异常性疼痛，并且与脊髓背角中HCN 2和HCN 4通道表达增加、cAMP产生增加和PKA蛋白表达增加有关，这些都被鞘内注射ZD 7288减弱。此外，鞘内注射SQ 22536和H-89显著降低DNP大鼠脊髓背角HCN 2和HCN 4通道的表达。本研究结果表明，脊髓背角HCN通道参与了DNP大鼠痛觉超敏的发病机制，并可能受到cAMP-PKA信号的调节。因此，HCN通道和cAMP-PKA信号传导是DNP患者中痛觉过敏治疗的潜在靶点。
The cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling acts a pivotal part in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels-mediated neuropathic and inflammatory pain. However, there has been no evidence of cAMP-PKA signaling is involved in regulation of spinal HCN channels function in the occurrence of diabetic neuropathic pain (DNP). The study aimed to elucidate the impact of HCN channels on neuropathic pain in a rat model of diabetes induced by streptozotocin, and whether cAMP-PKA signaling is involved in regulation of HCN channels function. In this report, we evaluated the effect of intrathecal administration of HCN channel blockers ZD7288, cAMP inhibitor SQ22536 and PKA inhibitor H-89 on nociceptive behavior in DNP rats. The mechanical withdrawal threshold (MWT) was measured to evaluate pain behavior in rats. Protein expression levels of HCN2, HCN4 channels and PKA in the spinal dorsal horn of rats were assessed. Furthermore, the levels of cAMP in rat spinal dorsal horn was analyzed. We discovered that DNP rats showed significant mechanical allodynia and are related to the increased HCN2 and HCN4 channels expression, enhanced cAMP production and elevated the expression of PKA protein in the spinal dorsal horn, which were attenuated by intrathecal ZD7288. Furthermore, intrathecal injection of SQ22536 and H-89 significantly reduced the HCN2 and HCN4 channels expression in the spinal dorsal horn of DNP rats. Our findings indicate that HCN channels of the spinal dorsal horn participate in the pathogenesis of allodynia in rats with DNP, which could be regulated by cAMP-PKA signaling. Therefore, HCN channels and cAMP-PKA signaling are potential targets for hyperalgesia treatment in DNP patients.