<br>小鼠和人脑中表达新型镇痛药物靶点生长抑素受体 4 的神经元的表征,International Journal of Molecular Sciences

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小鼠和人脑中表达新型镇痛药物靶点生长抑素受体 4 的神经元的表征
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2020-10-21 , DOI: 10.3390/ijms21207788
Angéla Kecskés _{1,

2} , Krisztina Pohóczky _{1,

2,

3} , Miklós Kecskés _{2,

4} , Zoltán V Varga _{5,

6} , Viktória Kormos _{1,

2} , Éva Szőke _{1,

2,

7} , Nóra Henn-Mike _{2,

8} , Máté Fehér ₉ , József Kun _{1,

2,

10} , Attila Gyenesei ₁₀ , Éva Renner ₁₁ , Miklós Palkovits ₁₁ , Péter Ferdinandy _{5,

12} , István M Ábrahám _{2,

8} , Balázs Gaszner _{2,

13} , Zsuzsanna Helyes _{1,

2,

7,

14}

Affiliation

Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, University of Pécs, H-7624 Pécs, Hungary.
Centre for Neuroscience, University of Pécs, H-7624 Pécs, Hungary.
Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary.
Institute of Physiology, Medical School & Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary.
Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary.
HCEMM-SU Cardiometabolic Immunology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary.
ALGONIST Biotechnologies GmbH, A-1030 Wien, Austria.
Institute of Physiology, Medical School & Szentágothai Research Centre, PTE-NAP Molecular Neuroendocrinology Research Group, University of Pécs, H-7624 Pécs, Hungary.
Department of Neurosurgery, Kaposi Mór Teaching Hospital, H-7400 Kaposvár, Hungary.
Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, Szentágothai Research Centre University of Pécs, H-7624 Pécs, Hungary.
Human Brain Tissue Bank, Semmelweis University, H-1089 Budapest, Hungary.
Pharmahungary Group, H-6720 Szeged, Hungary.
Department of Anatomy, Medical School, Research Group for Mood Disorders, University of Pécs, H-7624 Pécs, Hungary.
PharmInVivo Ltd., H-7629 Pécs, Hungary.

生长抑素是一种重要的情绪和疼痛调节神经肽，通过其 Gi 蛋白偶联受体亚型 4 (SST4) 发挥镇痛、抗炎和抗抑郁作用，而无需内分泌作用。 SST4 被认为是治疗慢性神经性疼痛和抑郁症（常见合并症）的独特新型药物靶点。然而，人们对它的神经元表达和细胞机制知之甚少。因此，我们的目标是（i）阐明 Sstr4/SSTR4 mRNA 的表达模式，（ii）从神经化学角度表征，以及（iii）从电生理学角度表征小鼠和人脑中表达 Sstr4/SSTR4 的神经元群。在这里，我们描述了小鼠伤害性和抗伤害性通路的细胞核以及人脑区域中的 SST4 表达模式，并提供了表达 SST4 的神经元的神经化学和电生理学特征。强烈或中度的 SST4 表达主要出现在疼痛基质主要成分的谷氨酸能神经元中，这些神经元也主要参与情绪调节。 SST4 激动剂 J-2156 通过增强去极化激活的非失活 K+ 电流（M 电流），从而显着降低 V 层锥体神经元的放电率，从而产生显着的抑制作用。这些是解释 SST4 激动剂作为新型镇痛和抗抑郁候选药物的作用机制的第一个转化结果。

"点击查看英文标题和摘要"

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains

Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates.

更新日期：2020-10-21

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