Inhibition of sigma-1 receptor reduces DRG cell apoptosis of rats with neuropathic pain

doi:10.16352/j.issn.1001-6325.2024.08.1101

Abstract

Abstract: Objective To investigate the effect of sigma-1 receptor (sig-1R) inhibition on apoptosis in the dorsal root ganglion (DRG) of rats with sciatic nerve chronic constriction injury (CCI)-mediated neuropathic pain. Methods Rats undergoing intrathecal intubation were randomly divided into three groups with 12 in each: sham group, model group (CCI modeling one week after intrathecal intubation) and sig-1R inhibitor group (BD1047 group) that was injected intrathecally on the fourth, fifth, and sixth days after the CCI operation. The mechanical withdrawal threshold (MWT) of rats was detected on the day before surgery and then first, third, fifth and seventh days after surgery. The expression of sig-1R, Bcl-2 and Bax was detected by Western blot and immunofluorescence in DRG cell; TUNEL staining microscopy was used to observe the apoptosis of DRG cells. The changes of endoplasmic reticulum and mitochondria were observed by transmission electron microscopy of DRG cells. Results Compared with the sham group, the model group showed a decreased MWT at all time points after surgery, up-regulation of DRG cell apoptosis, up-regulation of sig-1R and Bax, down-regulation of Bcl-2, swelling of endoplasmic reticulum, disruption of mitochondrial membrane and reduction of mitochondrial cristae in the DRG cell endoplasmic reticulum after surgery(P＜0.05).BD1047 group showed elevated MWT at the fifth and seventh postoperative days, down-regulation of DRG cell apoptosis, down-regulated expression of sig-1R and Box, up-regulated expression of Bcl-2 and slightly damaged endoplasmic reticulum as well as mitochondria of DRG cells compared with model group(P＜0.05). Conclusions Inhibition of sig-1R up-regulates mechanical withdrawal threshold and reduces DRG cell apoptosis in CCI rats.

Key words: neuropathic pain, sigma-1 receptor, dorsal root ganglion, apoptosis

CLC Number:

R614
R745

YU Dongling, MO Shaoe, FU Wen, CHEN Shi, XIE Chouqin, LAN Yuyan. Inhibition of sigma-1 receptor reduces DRG cell apoptosis of rats with neuropathic pain[J]. Basic & Clinical Medicine, 2024, 44(8): 1101-1106.

References

[1] Bouhassira D. Neuropathic pain: definition assessment and epidemiology[J]. Rev Neurol Paris, 2019,175:16-25.
[2] 吕彦函,余卓颖,李民.肠道菌群在神经病理性疼痛中作用的研究进展[J].基础医学与临床,2023,43:188-191.
[3] Delprat B, Crouzier L, Su TP, et al. At the crossing of ER stress and MAMs: a key role of Sigma-1 receptor?[J]. Adv Exp Med Biol, 2020, 1131: 699-718.
[4] 曹丹旎,吴宁,李锦. sigma-1受体生物学研究进展及对其与神经精神系统疾病关系的最新认识[J].中国药理学与毒理学杂志, 2022, 36: 881-902.
[5] 王娅,李瑞鑫,葛朝明. 瞬时受体电位通道与Sigma-1受体相互作用及其调控疼痛的研究进展[J].现代药物与临床,2024, 39:263-268.
[6] 傅文, 农小连, 刘可鹏, 等. GSK-3β在大鼠背根神经节神经元细胞内质网应激中的作用机制研究[J].广西医科大学学报, 2021, 38: 1871-1875.
[7] Hou Y, Wang L, Gao J, et al. A modified procedure for lumbar intrathecal catheterization in rats[J]. Neurol Res, 2016, 38:725-732.
[8] Nong X, Lan Y. Picroside II attenuates CCI-induced neuropathic pain in rats by inhibiting spinal reactive astrocyte-mediated neuroinflammation through the NF-κB pathway[J]. Neurochem Res, 2018, 43:1058-1066.
[9] 朱锋,钟粤,邓义江等.右美托咪定通过上调PPAR-γ改善神经病理性疼痛模型大鼠的痛觉敏化[J].基础医学与临床,2023,43:1369-1374.
[10] Choi JG, Choi SR, Kang DW, et al. Sigma-1 receptor increases intracellular calcium in cultured astrocytes and contributes to mechanical allodynia in a model of neuropathic pain[J]. Brain Res Bull, 2022, 178:69-81.
[11] Marcotti A, Fernández-Trillo J, González A, et al. TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy[J]. Brain, 2023, 146: 475-491.
[12] Fujii C, Zorumski CF, Izumi Y. Endoplasmic reticulum stress, autophagy, neuroinflammation, and sigma 1 receptors as contributors to depression and its treatment[J]. Neural Regen Res, 2024, 19: 2202-2211.
[13] Gris G, Portillo-Salido E, Aubel B, et al. The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats[J]. Sci Rep, 2016, 18: 24591. doi:10.1038/srep24591.
[14] Longhitano L, Castracani CC, Tibullo D, et al. Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma[J]. Oncotarget, 2017, 8: 91099-91111.
[15] Liu C, Chen IS, Tateyama M, et al. Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist[J]. J Biol Chem, 2024,300:107219. doi:10.1016/j.jbc.2024.107219.