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疼痛、内感受和情绪反应的神经生物学:神经生长因子依赖性神经元的启示。

Neurobiology of pain, interoception and emotional response: lessons from nerve growth factor-dependent neurons.

机构信息

Department of Pediatrics, Kumamoto University Hospital, Honjo 1-1-1, Chuou-ku, Kumamoto, 860-8556, Japan.

出版信息

Eur J Neurosci. 2014 Feb;39(3):375-91. doi: 10.1111/ejn.12448.

Abstract

Although nerve growth factor (NGF) is a well-known neurotrophic factor, it also acts as a mediator of pain, itch and inflammation. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder caused by loss-of-function mutations in NTRK1, the gene encoding a receptor tyrosine kinase for NGF, TrkA. Mutations in NTRK1 cause the selective loss of NGF-dependent neurons in otherwise intact systems. NGF-dependent primary afferents are thinly myelinated Aδ or unmyelinated C-fibers that are dependent on the NGF-TrkA system during development. In CIPA, the lack of pain and the presence of anhidrosis (inability to sweat) are due to the absence of both NGF-dependent primary afferents and sympathetic postganglionic neurons, respectively. These peripheral neurons form an interface between the nervous system and the 'body-proper' and play essential roles in the interoception and sympathetic regulation of various tissues or organs. Patients with CIPA also show mental retardation and characteristic behaviors and are probably neuron-deficient within the brain. However, the functions of NGF-dependent neurons in the brain are controversial, both in animal and in human studies. This review focuses on various brain regions that express TrkA mRNA, based on data from the Allen Human Brain Atlas, and discusses putative neuronal networks related to these brain regions in humans. A better understanding the distribution of NGF-dependent neurons in the brain will provide a framework for further studies to investigate pain, interoception and emotional responses. Furthermore, strategies targeting the molecular mechanisms through which the NGF-TrkA system functions may provide hope for the development of novel analgesics.

摘要

尽管神经生长因子 (NGF) 是一种众所周知的神经营养因子,但它也作为疼痛、瘙痒和炎症的介质发挥作用。先天性无痛无汗症 (CIPA) 是一种常染色体隐性遗传疾病,由编码 NGF 受体酪氨酸激酶 TrkA 的 NTRK1 基因的功能丧失突变引起。NTRK1 突变导致在其他完整系统中选择性丧失依赖于 NGF 的神经元。依赖于 NGF 的初级传入纤维是薄髓鞘 Aδ 或无髓鞘 C 纤维,在发育过程中依赖于 NGF-TrkA 系统。在 CIPA 中,疼痛缺失和无汗(无法出汗)是由于缺乏依赖于 NGF 的初级传入纤维和交感节后神经元所致。这些周围神经元形成了神经系统和“身体本身”之间的接口,在各种组织或器官的内脏感知和交感调节中发挥着重要作用。CIPA 患者还表现出智力迟钝和特征性行为,并且可能在大脑中缺乏神经元。然而,NGF 依赖性神经元在大脑中的功能在动物和人类研究中均存在争议。本综述基于艾伦人类大脑图谱的数据,重点讨论了表达 TrkA mRNA 的各种大脑区域,并讨论了与这些大脑区域相关的可能神经元网络。更好地了解大脑中依赖于 NGF 的神经元的分布将为进一步研究疼痛、内脏感知和情绪反应提供框架。此外,针对 NGF-TrkA 系统功能的分子机制的靶向策略可能为新型镇痛药的开发提供希望。

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