Shibata Yuto, Matsumoto Yuki, Kohno Keita, Nakashima Yasuharu, Tsuda Makoto
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Cells. 2025 May 2;14(9):666. doi: 10.3390/cells14090666.
Neuropathic pain results from a lesion or disease affecting the somatosensory nervous system. Injury to primary afferent nerves leads to microgliosis in the spinal dorsal horn (SDH), which plays a crucial role in developing neuropathic pain. Within the SDH, primary afferent fibers broadly project, and microglia are nearly ubiquitously distributed under normal conditions. However, not all microglia react to injuries affecting primary afferent fibers, resulting in spatially heterogeneous microgliosis within the SDH. The mechanisms underlying this phenomenon remain elusive. In this study, the spatial relationship between microgliosis and the projections of injured nerves was investigated by generating mice that had expressed tdTomato in the fourth lumbar dorsal root ganglion (L4-DRG) neurons via intra-L4-spinal nerve (SpN) injection of adeno-associated viral vectors. After transection of the L4-SpN, we found that microgliosis in the SDH selectively occurred in the innervation territories of the injured primary afferent fibers. However, denervating transient receptor potential vanilloid 1 (TRPV1)-expressing primary afferent fibers in the SDH through intrathecal injection of capsaicin did not trigger microgliosis, nor did it influence the microgliosis induced by L4-SpN injury. Conversely, pharmacological damage to myelinated DRG neurons, including Aβ-fibers, was sufficient to induce microgliosis. Furthermore, L4-SpN injury also induced microgliosis in the gracile nucleus, which primarily receives innervation from Aβ-fibers. These findings suggest that microgliosis in the SDH shortly after peripheral nerve injury is predominantly associated with damage to primary afferent Aβ-fibers.
神经性疼痛源于影响躯体感觉神经系统的损伤或疾病。初级传入神经损伤会导致脊髓背角（SDH）的小胶质细胞增生，这在神经性疼痛的发生中起关键作用。在SDH内，初级传入纤维广泛投射，小胶质细胞在正常情况下几乎普遍分布。然而，并非所有小胶质细胞都会对影响初级传入纤维的损伤产生反应，导致SDH内小胶质细胞增生在空间上具有异质性。这种现象背后的机制仍然难以捉摸。在本研究中，通过经腰4脊髓神经（SpN）注射腺相关病毒载体，使腰4背根神经节（L4-DRG）神经元中表达tdTomato的小鼠，来研究小胶质细胞增生与受损神经投射之间的空间关系。切断L4-SpN后，我们发现SDH中的小胶质细胞增生选择性地发生在受损初级传入纤维的支配区域。然而，通过鞘内注射辣椒素使SDH中表达瞬时受体电位香草酸亚型1（TRPV1）的初级传入纤维失神经支配，并未引发小胶质细胞增生，也未影响L4-SpN损伤诱导的小胶质细胞增生。相反，对包括Aβ纤维在内的有髓DRG神经元进行药理学损伤足以诱导小胶质细胞增生。此外，L4-SpN损伤还诱导了薄束核中的小胶质细胞增生，薄束核主要接受Aβ纤维的支配。这些发现表明，外周神经损伤后不久SDH中的小胶质细胞增生主要与初级传入Aβ纤维的损伤有关。
