Neurosciences & Mental Health Program, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Neurosciences & Mental Health Program, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Cell Rep. 2024 Jun 25;43(6):114293. doi: 10.1016/j.celrep.2024.114293. Epub 2024 May 29.
Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular process of autophagy, is involved in pain processing and is targetable for pain relief. We find that monoallelic deletion of Becn1 increases inflammation-induced mechanical hypersensitivity in male mice. However, in females, loss of Becn1 does not affect inflammation-induced mechanical hypersensitivity. In males, intrathecal delivery of a Beclin 1 activator, tat-beclin 1, reverses inflammation- and nerve injury-induced mechanical hypersensitivity and prevents mechanical hypersensitivity induced by brain-derived neurotrophic factor (BDNF), a mediator of inflammatory and neuropathic pain. Pain signaling pathways converge on the enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. The loss of Becn1 upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. We conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males.
慢性疼痛与基本细胞过程的改变有关。在这里，我们研究了 Beclin 1 蛋白是否参与疼痛处理，Beclin 1 蛋白是启动细胞自噬过程所必需的蛋白质，并且是缓解疼痛的靶标。我们发现，Beclin 1 的单等位基因缺失会增加雄性小鼠炎症引起的机械性超敏反应。然而，在雌性小鼠中，Beclin 1 的缺失并不影响炎症引起的机械性超敏反应。在雄性小鼠中，鞘内给予 Beclin 1 激活剂 tat-beclin 1 可逆转炎症和神经损伤引起的机械性超敏反应，并可预防脑源性神经营养因子（BDNF）引起的机械性超敏反应，BDNF 是炎症和神经病理性疼痛的介质。疼痛信号通路集中在脊髓背角神经元中 N-甲基-D-天冬氨酸受体（NMDAR）的增强上。Beclin 1 的缺失会增加雄性而非雌性背角神经元中突触 NMDAR 介导的电流。我们得出结论，抑制背角中的 Beclin 1 对介导雄性的炎症和神经病理性疼痛信号通路至关重要。
