Spinal cord interneurons expressing the gastrin-releasing peptide receptor convey itch through VGLUT2-mediated signaling.
Spinal cord interneurons expressing the gastrin-releasing peptide receptor convey itch through VGLUT2-mediated signaling.
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DOI：
10.1097/j.pain.0000000000000861
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发表时间：
2017-05
期刊：
影响因子：
7.4
通讯作者：
Lagerström MC
中科院分区：
文献类型：
--
作者：
Aresh B;Freitag FB;Perry S;Blümel E;Lau J;Franck MCM;Lagerström MC
补充数字内容可在正文中找到。胃泌素释放肽受体表达细胞是中间神经元，使用谷氨酸将化学瘙痒的感觉传递到脊髓瘙痒标记线的下一步。瘙痒是一种促进抓挠欲望的感觉，这种感觉可以由机械和化学刺激引起。在脊髓中，表达胃泌素释放肽受体(GRPR)的神经元被认为是瘙痒的特异性介质。然而，我们对脊髓中的GRPR群体，以及这些神经元如何行使其功能的了解是有限的。为此，我们构建了一条针对GRPR神经元群体的Cre品系(GRPR-Cre)。我们的分析表明，脊髓中的GRPR-CRE细胞主要是位于背板，尤其是II-IV板层的兴奋性中间神经元。应用特异性激动剂胃泌素释放肽可在43.3%的GRPR-CRE神经元中产生棘波反应，其中大多数细胞表现出紧张性放电特性。此外，我们的分析表明，GRPR-Cre群体表达Vlu2 mRNA，在GRPR-Cre细胞(Vlos2-lox；GRPR-Cre小鼠)中，Vlu2被去除的小鼠表现出较少的自发性瘙痒和对组胺能和非组胺能药物的减弱反应。我们还可以证明，应用瘙痒诱导肽，利钠多肽B，可以诱导GRPR-CRE神经元亚群的钙内流。综上所述，我们的数据表明，GRPR-CRE脊髓神经群由中间神经元组成，这些中间神经元使用VGLUT2介导的信号将化学和自发的瘙痒刺激传递给下一个目前未知的瘙痒标记线上的神经元。
Supplemental Digital Content is Available in the Text. Gastrin-releasing peptide receptor–expressing cells are interneurons that use glutamate to transmit the perception of chemical itch to the next step in the labeled line of itch in the spinal cord. Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox;Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.