Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.
Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.
复制标题
表达CGRP的背角中间神经元对机械灵敏度的贡献。
DOI：
10.7554/elife.59751
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发表时间：
2021-06-01
期刊：
影响因子：
7.7
通讯作者：
Basbaum A
中科院分区：
文献类型：
--
作者：
Löken LS;Braz JM;Etlin A;Sadeghi M;Bernstein M;Jewell M;Steyert M;Kuhn J;Hamel K;Llewellyn-Smith IJ;Basbaum A
初级感觉神经元通常被认为是背角降钙素基因相关肽（CGRP）的唯一来源，CGRP是一种对疼痛信息传递至关重要的神经肽。使用他莫昔芬诱导的CalcaCreER转基因小鼠，在这里，我们确定了一个独特的人群CGRP表达兴奋性中间神经元在第三层的脊髓背角和三叉神经核尾侧。这些中间神经元具有背侧定向的树突和腹侧定向的轴突。在静息状态下，CGRP中间神经元处于紧张性抑制控制下，无论是无害的还是有害的刺激都不会引起这些神经元中显著的Fos表达。然而，背根的同步电非伤害性Aβ初级传入刺激使CGRP中间神经元去极化，与它们接受VGLUT 1神经支配一致。另一方面，神经元的化学激活产生了机械过敏反应，以响应冯弗雷刺激，而他们的半胱天冬酶介导的消融导致机械敏感性降低。最后，在部分周围神经损伤后，无害刺激（刷）诱导CGRP中间神经元的Fos表达显着。这些研究结果表明，CGRP中间神经元变得过度兴奋，并有助于无论是上行电路起源于深背角或反射电路在基线条件下，但不是在设置的神经损伤。感知疼痛的能力对我们的生存至关重要。通常，疼痛是由高温或低温，强力或化学刺激引起的，例如辣椒素，辣椒中的疼痛刺激物质。然而，如果手臂或腿部的神经纤维受损，通常无痛的触摸或压力刺激会引起疼痛。这种超敏反应被称为机械性异常性疼痛。一种称为降钙素基因相关肽（CGRP）的蛋白质与机械性异常性疼痛和其他慢性疼痛（如偏头痛）有关。CGRP存在于神经元中，并从神经元中释放出来，神经元接收和传递来自组织（如皮肤和肌肉）的疼痛信息到脊髓。然而，只有少数不同的CGRP表达神经元组已被确定，目前还不清楚，如果这些神经细胞也有助于机械异常性疼痛。为了研究这一点，Löken等人对小鼠进行了基因工程改造，使所有含有CGRP的神经细胞在用激光照射时产生红色荧光。这包括一组以前未被探索的表达CGRP的神经元，这些神经元在脊髓的一部分中被发现，已知这些神经元接收有关非疼痛刺激的信息。使用神经解剖学方法，Löken等人监测了这些神经元在部分神经损伤之前和之后对各种刺激的反应。这种部分损伤是通过手术引起的，手术切断了一条关键腿神经的几个分支，但不是全部。实验表明，在正常状态下，表达CGRP的神经元对机械刺激几乎没有反应。事实上，很难确定他们通常会对什么做出反应。然而，在神经损伤后，刷小鼠的皮肤引起这些细胞的显着活动。此外，当这些CGRP细胞被人工刺激时，刺激会诱导对机械刺激的超敏反应，即使小鼠没有神经损伤。这些结果表明，这组神经元，这是正常抑制，可以成为过度兴奋，并有助于机械异常性疼痛的发展。总之，Löken等人已经确定了脊髓中的一组神经细胞，它们处理机械信息并导致触摸诱发的疼痛。未来的研究将确定由这些神经细胞释放的CGRP靶向的神经回路。这些回路代表了用于管理与神经损伤相关的慢性疼痛病症的新治疗靶点，特别是机械性异常性疼痛，这是慢性疼痛患者最常见的主诉。
Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury. The ability to sense pain is critical to our survival. Normally, pain is provoked by intense heat or cold temperatures, strong force or a chemical stimulus, for example, capsaicin, the pain-provoking substance in chili peppers. However, if nerve fibers in the arms or legs are damaged, pain can occur in response to touch or pressure stimuli that are normally painless. This hypersensitivity is called mechanical allodynia. A protein called calcitonin gene-related peptide, or CGRP, has been implicated in mechanical allodynia and other chronic pain conditions, such as migraine. CGRP is found in, and released from, the neurons that receive and transmit pain messages from tissues, such as skin and muscles, to the spinal cord. However, only a few distinct groups of CGRP-expressing neurons have been identified and it is unclear if these nerve cells also contribute to mechanical allodynia. To investigate this, Löken et al. genetically engineered mice so that all nerve cells containing CGRP produced red fluorescent light when illuminated with a laser. This included a previously unexplored group of CGRP-expressing neurons found in a part of the spinal cord that is known to receive information about non-painful stimuli. Using neuroanatomical methods, Löken et al. monitored the activity of these neurons in response to various stimuli, before and after a partial nerve injury. This partial injury was induced via a surgery that cut off a few, but not all, branches of a key leg nerve. The experiments showed that in their normal state, the CGRP-expressing neurons hardly responded to mechanical stimulation. In fact, it was difficult to establish what they normally respond to. However, after a nerve injury, brushing the mice’s skin evoked significant activity in these cells. Moreover, when these CGRP cells were artificially stimulated, the stimulation induced hypersensitivity to mechanical stimuli, even when the mice had no nerve damage. These results suggest that this group of neurons, which are normally suppressed, can become hyperexcitable and contribute to the development of mechanical allodynia. In summary, Löken et al. have identified a group of nerve cells in the spinal cord that process mechanical information and contribute to touch-evoked pain. Future studies will identify the nerve circuits that are targeted by CGRP released from these nerve cells. These circuits represent a new therapeutic target for managing chronic pain conditions related to nerve damage, specifically mechanical allodynia, which is the most common complaint of patients with chronic pain.