Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, 18016, Spain.
Institute of Neuroscience, Biomedical Research Center, University of Granada, Armilla, Granada, 18100, Spain.
J Neuroimmune Pharmacol. 2024 Aug 20;19(1):46. doi: 10.1007/s11481-024-10144-8.
The mechanisms for neuropathic pain amelioration by sigma-1 receptor inhibition are not fully understood. We studied genome-wide transcriptomic changes (RNAseq) in the dorsal root ganglia (DRG) from wild-type and sigma-1 receptor knockout mice prior to and following Spared Nerve Injury (SNI). In wildtype mice, most of the transcriptomic changes following SNI are related to the immune function or neurotransmission. Immune function transcripts contain cytokines and markers for immune cells, including macrophages/monocytes and CD4 + T cells. Many of these immune transcripts were attenuated by sigma-1 knockout in response to SNI. Consistent with this we found, using flow cytometry, that sigma-1 knockout mice showed a reduction in macrophage/monocyte recruitment as well as an absence of CD4 + T cell recruitment in the DRG after nerve injury. Sigma-1 knockout mice showed a reduction of neuropathic (mechanical and cold) allodynia and spontaneous pain-like responses (licking of the injured paw) which accompany the decreased peripheral neuroinflammatory response after nerve injury. Treatment with maraviroc (a CCR5 antagonist which preferentially inhibits CD4 + T cells in the periphery) of neuropathic wild-type mice only partially replicated the sigma-1 knockout phenotype, as it did not alter cold allodynia but attenuated spontaneous pain-like responses and mechanical hypersensitivity. Therefore, modulation of peripheral CD4 + T cell activity might contribute to the amelioration of spontaneous pain and neuropathic tactile allodynia seen in the sigma-1 receptor knockout mice, but not to the effect on cold allodynia. We conclude that sigma-1 receptor inhibition decreases DRG neuroinflammation which might partially explain its anti-neuropathic effect.
sigma-1 受体抑制减轻神经病理性疼痛的机制尚未完全阐明。我们研究了野生型和 sigma-1 受体敲除小鼠在 spared nerve injury (SNI) 前后背根神经节 (DRG) 的全基因组转录组变化 (RNAseq)。在野生型小鼠中，SNI 后大多数转录组变化与免疫功能或神经传递有关。免疫功能转录物包含细胞因子和免疫细胞标志物，包括巨噬细胞/单核细胞和 CD4+T 细胞。这些免疫转录物中的许多在 sigma-1 敲除后对 SNI 的反应减弱。通过流式细胞术，我们发现 sigma-1 敲除小鼠在神经损伤后 DRG 中的巨噬细胞/单核细胞募集减少，并且 CD4+T 细胞募集缺失。sigma-1 敲除小鼠表现出神经病理性（机械性和冷性）痛觉过敏和自发性疼痛样反应（受伤爪子的舔舐）减少，这伴随着外周神经炎症反应的减少。对神经病理性野生型小鼠用 maraviroc（一种 CCR5 拮抗剂，优先抑制外周的 CD4+T 细胞）治疗仅部分复制了 sigma-1 敲除小鼠的表型，因为它不会改变冷觉过敏，但减轻了自发性疼痛样反应和机械性超敏反应。因此，外周 CD4+T 细胞活性的调节可能有助于减轻 sigma-1 受体敲除小鼠中观察到的自发性疼痛和神经病理性触觉过敏，但对冷觉过敏无影响。我们得出结论，sigma-1 受体抑制降低了 DRG 神经炎症，这可能部分解释了其抗神经病理性作用。
