Implication of system xc− in complete Freund's adjuvant-induced peripheral inflammation and associated nociceptive sensitization

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Pauline Beckers , Mathilde Charlier , Lorie Azria-Richter , Pauline Braconnier , Nathalie Desmet , Ann Massie , Emmanuel Hermans
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引用次数: 0

Abstract

Background

Persistent inflammation leading to neuronal sensitization in pain pathways, are key features of chronic inflammatory pain. Alike macrophages in the periphery, glial cells exacerbate hypersensitivity by releasing proalgesic mediators in the central nervous system. Expressed by peripheral and central immune cells, the cystine-glutamate antiporter system xc plays a significant role in inflammatory responses, but its involvement in chronic inflammatory pain remains underexplored. We herein investigated the contribution of this exchanger in nociceptive hypersensitivity triggered by a peripheral inflammatory insult.

Methods

Complete Freund's adjuvant (CFA) was injected into the left hind paw of wild-type C57Bl/6 female mice, of xCT-deficient mice (specific subunit of system xc) and of mice receiving the system xc inhibitor sulfasalazine. Paw edema was measured over three weeks and pain-associated behaviors were evaluated. Additionally, pro-inflammatory cytokine levels were assessed in blood samples.

Results

CFA injection led to a persistent increase in paw edema and hypersensitivity to mechanical and thermal stimuli, which were less pronounced in xCT-deficient mice. This reduced sensitivity was accompanied by lower systemic pro-inflammatory cytokine levels in xCT-deficient mice. Accordingly, pharmacological inhibition of system xc with sulfasalazine, either before or after pain induction, efficiently reduced the algesic and inflammatory responses to CFA in wild-type mice.

Conclusion

Our findings reveal a critical role for system xc in the pathophysiology of inflammatory pain. xCT deficiency reduces pain behaviors and peripheral inflammation, positioning system xc as a promising therapeutic target for alleviating chronic inflammatory pain.
系统xc-在完全弗氏佐剂诱导外周炎症和相关伤害性致敏的意义。
背景:持续的炎症导致疼痛通路中的神经元致敏,是慢性炎症性疼痛的关键特征。与外周巨噬细胞一样,神经胶质细胞通过释放中枢神经系统的促痛介质而加剧超敏反应。胱氨酸-谷氨酸反转运系统xc-由外周和中枢免疫细胞表达,在炎症反应中起重要作用,但其在慢性炎症性疼痛中的作用仍未得到充分研究。我们在此研究了这种交换在由外周炎症性损伤引发的伤害性超敏反应中的作用。方法:将完全弗氏佐剂(CFA)注射到野生型C57Bl/6雌性小鼠、xct缺陷小鼠(xc-系统的特定亚单位)和xc-系统抑制剂磺胺吡啶小鼠的左后爪。在三周内测量足跖水肿,并评估疼痛相关行为。此外,还评估了血液样本中的促炎细胞因子水平。结果:CFA注射导致脚掌水肿持续增加,对机械和热刺激过敏,而在xct缺陷小鼠中不太明显。在xct缺陷小鼠中,这种敏感性降低伴随着较低的全身促炎细胞因子水平。因此,在疼痛诱导之前或之后,用柳氮磺胺吡啶对xc-系统进行药理学抑制,有效地降低了野生型小鼠对CFA的疼痛和炎症反应。结论:我们的研究结果揭示了xc-系统在炎症性疼痛的病理生理中起着关键作用。xCT缺乏可减少疼痛行为和外周炎症,定位系统xc-为缓解慢性炎症性疼痛的有希望的治疗靶点。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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