Myocardium ischemia-reperfusion injury (IRI) is the major cause of postoperative cardiac dysfunction. While intrathecal morphine preconditioning (ITMP) can reduce IRI in animals, the molecular processes underlying IRI and ITMP remain elusive. Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed in cardiac sensory neurons and has a crucial role in detecting myocardial ischemia. This study aimed to determine the role of up-regulated dorsal root ganglion (DRG)-TRPV1 in IRI and whether its inhibition contributes to ITMP-induced cardioprotection. Animal model of IRI was established by left coronary artery occlusion (30 min) and reperfusion (2 h) in rats. Intrathecal intubation was prepared for morphine preconditioning, TRPV1-shRNA or selective TRPV1 antagonist administration. After IRI, both protein and phosphorylation levels of TRPV1 were significantly increased, and the immunofluorescence intensity of TRPV1 was increased and colocalized with μ-opioid receptors in DRG. Intrathecal pre-administration of either TRPV1-shRNA or TRPV1 antagonist significantly reduced myocardial injury and the upregulation of TRPV1 in DRG induced by IRI. Simultaneously, ITMP significantly suppressed TRPV1 protein expression and phosphorylation in DRG, as well as the heart infarct size and arrhythmia score caused by IRI. The suppression of TRPV1 elevation and activation by ITMP were reversed by intrathecal injection of the selective μ receptor antagonist. Furthermore, IRI elevated DRG cAMP, while intrathecal administration of the selective cAMP-PKA inhibitor reduced myocardial injury. Finally, we showed that activation of opioid receptor by morphine inhibited PKA activator-induced TRPV1 channel activity at the cellular level. These findings suggest that the elevation and activation of TRPV1 in DRG during myocardial ischemia-reperfusion might be responsible for cardiac injury. ITMP exerts cardioprotection by inhibiting DRG-TRPV1 activity via modulation cAMP. Therefore, inhibition of TRPV1 upregulation in DRG might be used as a novel therapeutic mechanism for myocardium ischemia-reperfusion injury.

中文翻译：

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在心肌缺血中抑制DRG-TRPV1上调有助于外源性心脏保护。

心肌缺血再灌注损伤（IRI）是术后心脏功能障碍的主要原因。尽管鞘内吗啡预处理（ITMP）可以减少动物的IRI，但IRI和ITMP的分子过程仍然难以捉摸。瞬态受体电位类香草素1型（TRPV1）在心脏感觉神经元中高度表达，在检测心肌缺血中起关键作用。这项研究旨在确定上调的背根神经节（DRG）-TRPV1在IRI中的作用以及其抑制作用是否有助于ITMP诱导的心脏保护作用。通过大鼠左冠状动脉闭塞（30分钟）和再灌注（2 h）建立IRI动物模型。鞘内插管可用于吗啡预处理，TRPV1-shRNA或选择性TRPV1拮抗剂给药。在IRI之后，TRPV1的蛋白质和磷酸化水平均显着增加，并且TRPV1的免疫荧光强度增加并与DRG中的μ阿片受体共定位。鞘内预先给予TRPV1-shRNA或TRPV1拮抗剂可显着降低IRI诱导的DRG中的心肌损伤和TRPV1的上调。同时，ITMP显着抑制了DRG中TRPV1蛋白的表达和磷酸化，以及IRI引起的心脏梗死面积和心律失常评分。通过鞘内注射选择性μ受体拮抗剂可以逆转ITMP对TRPV1升高的抑制和激活。此外，IRI升高了DRG cAMP，而鞘内注射选择性cAMP-PKA抑制剂可减轻心肌损伤。最后，我们发现吗啡激活阿片样物质受体在细胞水平上抑制了PKA激活剂诱导的TRPV1通道活性。这些发现表明，心肌缺血再灌注过程中DRG中TRPV1的升高和激活可能是心脏损伤的原因。ITMP通过调节cAMP抑制DRG-TRPV1活性来发挥心脏保护作用。因此，抑制DRG中TRPV1的上调可能被用作心肌缺血再灌注损伤的新治疗机制。