对大鼠脑内氯胺酮类似物 SN 35210 和 SN 35563 反应的转录变化。
Transcriptional changes in response to ketamine ester-analogs SN 35210 and SN 35563 in the rat brain.
机构信息
Faculty of Science and Engineering, The University of Waikato, Hillcrest, Hamilton, 3216, New Zealand.
Waikato District Health Board, Pembroke Street, Hamilton, 3204, New Zealand.
出版信息
BMC Genomics. 2019 Apr 11;20(1):281. doi: 10.1186/s12864-019-5649-6.
BACKGROUND
Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared across four relevant target regions of the rat brain.
RESULTS
SN 35563 produced large-scale alteration of gene expression in the Basolateral Amygdala (BLA) and Paraventricular Nucleus of the Thalamus (PVT), in excess of 10x that induced by ketamine and SN 35210. A smaller and quantitatively similar number of gene changes were observed in the Insula (INS) and Nucleus Accumbens (ACB) for all three agents. In the BLA and PVT, SN 35563 caused enrichment for gene pathways related to the function and structure of glutamatergic synapses in respect to: release of neurotransmitter, configuration of postsynaptic AMPA receptors, and the underlying cytoskeletal scaffolding and alignment.
CONCLUSION
The analgesic ketamine ester analog SN 35563 induces profound large-scale changes in gene expression in key pain-related brain regions reflecting its unique prolonged pharmacodynamic profile.
背景
氯胺酮酯类似物 SN 35210 和 SN 35563 在动物模型中表现出与氯胺酮不同的药理学特征。两者都能诱导催眠，且催眠效果迅速消退，但矛盾的是，SN35563 却能诱导长时间的抗伤害感受状态。为了探究其潜在机制，我们在大鼠脑内四个相关靶区比较了广泛的转录组变化。
结果
SN 35563 引起了杏仁基底外侧核（BLA）和丘脑室旁核（PVT）内大规模的基因表达改变，其程度超过了氯胺酮和 SN 35210 引起的改变的 10 倍。在岛叶（INS）和伏隔核（ACB）中，所有三种药物都观察到数量较小但数量相似的基因变化。在 BLA 和 PVT 中，SN 35563 引起了与谷氨酸能突触功能和结构相关的基因途径的富集，包括神经递质的释放、突触后 AMPA 受体的构象以及潜在的细胞骨架支架和排列。
结论
镇痛用氯胺酮酯类似物 SN 35563 在关键的与疼痛相关的脑区引起了深刻的、大规模的基因表达变化，反映了其独特的、持久的药效学特征。
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