疼痛是一种复杂的感知,涉及令人不快的体感和情感体验。然而,介导其不同成分的潜在机制尚不清楚.1-磷酸鞘氨醇(S1P),鞘磷脂的代谢产物和有效的脂质介质,通过细胞表面的G蛋白偶联受体(S1PRs)启动信号传导。它在细胞增殖和凋亡等过程中充当第二信使。然而,神经药理学在中枢神经系统疼痛中的鞘脂信号仍未被研究和争议。
通过向左后爪足底内注射20μL完全弗氏佐剂(CFA)在体内诱导慢性伤害性疼痛模型。我们评估了CFA模型小鼠脊髓中S1P和S1PR1的表达。在CFA模型建立后,每天施用S1PR1或S1PR1特异性siRNA的功能拮抗剂。测量爪退缩反应频率(PWF)和爪退缩潜伏期(PWL)以评估机械性异常疼痛和热痛觉过敏,分别。RT-PCR评估白细胞介素(IL)-1β,IL-6和肿瘤坏死因子(TNF)-α水平。免疫印迹和免疫荧光分析胶质纤维酸性蛋白(GFAP),离子化钙结合接头分子(Iba1),STAT3,ERK,p38MAPK蛋白表达。
■在CFA诱导的慢性伤害性疼痛模型中,S1P和S1PR1表达水平显著升高,导致脊髓胶质细胞的激活。S1PR1活化还促进MMP2介导的成熟IL-1β的裂解。此外,S1PR1激活上调STAT3、ERK、和p38MAPK在神经胶质细胞,深刻影响下游信号通路并导致慢性伤害性疼痛。
■S1P/S1PR1轴在伤害性疼痛的细胞和分子机制中起关键作用。该信号通路调节神经胶质细胞活化和疼痛相关基因的表达(STAT3,ERK,p38MAPK)和脊髓背角的炎症因子。这些发现强调了靶向S1P系统开发新型镇痛疗法的潜力。
UNASSIGNED: Pain is a complex perception involving unpleasant somatosensory and emotional experiences. However, the underlying mechanisms that mediate its different components remain unclear. Sphingosine-1-phosphate (
S1P), a metabolite of sphingomyelin and a potent lipid mediator, initiates signaling via G protein-coupled receptors (S1PRs) on cell surfaces. It serves as a second messenger in cellular processes such as proliferation and apoptosis. Nevertheless, the neuropharmacology of sphingolipid signaling in pain conditions within the central nervous system remains largely unexplored and controversial.
UNASSIGNED: Chronic nociceptive pain models were induced in vivo by intraplantar injection of 20 μL complete Freund\'s adjuvant (CFA) into the left hind paws. We assessed
S1P and S1PR1 expression in the spinal cords of CFA model mice. Functional antagonists of S1PR1 or S1PR1-specific siRNA were administered daily following CFA model establishment. Paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL) were measured to evaluate mechanical allodynia and thermal hyperalgesia, respectively. RT-PCR assessed interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels. Western blotting and immunofluorescence were used to analyze glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), STAT3, ERK, and p38 MAPK protein expression.
UNASSIGNED: In the chronic nociceptive pain model induced by CFA,
S1P and S1PR1 expression levels were significantly elevated, leading to activation of spinal cord glial cells. S1PR1 activation also promoted MMP2-mediated cleavage of mature IL-1β. Additionally, S1PR1 activation upregulated phosphorylation of STAT3, ERK, and p38 MAPK in glial cells, profoundly impacting downstream signaling pathways and contributing to chronic nociceptive pain.
UNASSIGNED: The
S1P/S1PR1 axis plays a pivotal role in the cellular and molecular mechanisms underlying nociceptive pain. This signaling pathway modulates glial cell activation and the expression of pain-related genes (STAT3, ERK, p38 MAPK) and inflammatory factors in the spinal dorsal horn. These findings underscore the potential of targeting the
S1P system for developing novel analgesic therapies.