Zhang Ke, Ren Yu-Qing, Xue Yan, Duan Dongxia, Zhou Tong, Ding Ying-Zhuo, Li Xiang, Gong Wan-Kun, Guan Jiao-Qiong, Ma Le
Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Pharmacol. 2024 Mar 21;15:1359319. doi: 10.3389/fphar.2024.1359319. eCollection 2024.
The α2-adrenoceptor agonist dexmedetomidine is a commonly used drug for sedatives in clinics and has analgesic effects; however, its mechanism of analgesia in the spine remains unclear. In this study, we systematically used behavioural and transcriptomic sequencing, pharmacological intervention, electrophysiological recording and ultrasound imaging to explore the analgesic effects of the α2-adrenoceptor and its molecular mechanism. Firstly, we found that spinal nerve injury changed the spinal transcriptome expression, and the differential genes were mainly related to calcium signalling and tissue metabolic pathways. In addition, α2-adrenoceptor mRNA expression was significantly upregulated, and α2-adrenoceptor was significantly colocalised with markers, particularly neuronal markers. Intrathecal dexmedetomidine suppressed neuropathic pain and acute inflammatory pain in a dose-dependent manner. The transcriptome results demonstrated that the analgesic effect of dexmedetomidine may be related to the modulation of neuronal metabolism. Weighted gene correlation network analysis indicated that turquoise, brown, yellow and grey modules were the most correlated with dexmedetomidine-induced analgesic effects. Bioinformatics also annotated the involvement of metabolic processes and neural plasticity. A cardiovascular-mitochondrial interaction was found, and ultrasound imaging revealed that injection of dexmedetomidine significantly enhanced spinal cord perfusion in rats with neuropathic pain, which might be regulated by pyruvate dehydrogenase kinase 4 (pdk4), cholesterol 25-hydroxylase (ch25 h) and GTP cyclohydrolase 1 (gch1). Increasing the perfusion doses of dexmedetomidine significantly suppressed the frequency and amplitude of spinal nerve ligation-induced miniature excitatory postsynaptic currents. Overall, dexmedetomidine exerts analgesic effects by restoring neuronal metabolic processes through agonism of the α2-adrenoceptor and subsequently inhibiting changes in synaptic plasticity.
α2肾上腺素能受体激动剂右美托咪定是临床上常用的镇静药物，具有镇痛作用；然而，其在脊髓中的镇痛机制尚不清楚。在本研究中，我们系统地运用行为学和转录组测序、药理学干预、电生理记录以及超声成像等方法，探究α2肾上腺素能受体的镇痛作用及其分子机制。首先，我们发现脊髓神经损伤改变了脊髓转录组表达，差异基因主要与钙信号传导和组织代谢途径相关。此外，α2肾上腺素能受体mRNA表达显著上调，且α2肾上腺素能受体与标志物，尤其是神经元标志物显著共定位。鞘内注射右美托咪定以剂量依赖的方式抑制神经性疼痛和急性炎性疼痛。转录组结果表明，右美托咪定的镇痛作用可能与神经元代谢的调节有关。加权基因共表达网络分析表明，绿松石色、棕色、黄色和灰色模块与右美托咪定诱导的镇痛作用相关性最强。生物信息学还注释了代谢过程和神经可塑性的参与情况。发现了心血管-线粒体相互作用，超声成像显示，注射右美托咪定可显著增强神经性疼痛大鼠的脊髓灌注，这可能受丙酮酸脱氢酶激酶4（pdk4）、胆固醇25-羟化酶（ch25h）和GTP环化水解酶1（gch1）的调节。增加右美托咪定的灌注剂量可显著抑制脊髓神经结扎诱导的微小兴奋性突触后电流的频率和幅度。总体而言，右美托咪定通过激动α2肾上腺素能受体恢复神经元代谢过程，进而抑制突触可塑性变化，发挥镇痛作用。
