The nitroxyl donor, Angeli's salt, reduces chronic constriction injury-induced neuropathic pain.
The nitroxyl donor, Angeli's salt, reduces chronic constriction injury-induced neuropathic pain.
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DOI：
10.1016/j.cbi.2016.06.009
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发表时间：
2016-08-25
影响因子：
5.1
通讯作者：
Verri WA Jr
中科院分区：
文献类型：
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作者：
Longhi-Balbinot DT;Rossaneis AC;Pinho-Ribeiro FA;Bertozzi MM;Cunha FQ;Alves-Filho JC;Cunha TM;Peron JP;Miranda KM;Casagrande R;Verri WA Jr
慢性疼痛是世界范围内的主要健康问题。我们最近证明了硝酰基供体Angeli盐（AS）在炎症性疼痛模型中的镇痛作用。本研究采用小鼠坐骨神经慢性压迫性损伤（CCI）模型，观察了AS的急、慢性镇痛作用。急性（CCI后第7天）AS治疗（1和3 mg/kg; s.c.）减少CCI诱导的机械性痛觉过敏，但不减少热痛觉过敏。用1H-[1，2，4]恶二唑并[4，3，-a]喹喔啉-1-酮（ODQ，一种可溶性鸟苷酸环化酶抑制剂）、KT 5823（一种蛋白激酶G [PKG]抑制剂）或格列本脲（GLB，一种ATP敏感性钾通道阻滞剂）治疗可阻止AS的急性镇痛作用。用AS（3mg/kg，s.c.）促进持续减少CCI诱导的机械和热痛觉过敏。急性AS治疗降低CCI诱导的脊髓同种异体移植物炎性因子1（称为Iba-1）、白细胞介素-1 β（IL-1β）和ST 2受体mRNA表达。慢性AS治疗降低CCI诱导的脊髓胶质细胞酸性蛋白（GFAP）、Iba-1、IL-1β、肿瘤坏死因子-α（TNF-α）、白细胞介素-33（IL-33）和ST 2 mRNA表达。AS长期治疗（3 mg/kg，皮下注射）不改变天冬氨酸转氨酶、丙氨酸转氨酶、尿素或肌酐血浆水平。总之，这些结果表明，AS的急性镇痛作用依赖于激活cGMP/PKG/ATP敏感性钾通道信号通路。此外，慢性AS通过减少脊髓小胶质细胞和星形胶质细胞的活化，降低TNF-α、IL-1β和IL-33细胞因子的表达，减轻CCI诱导的机械和热痛觉过敏。这种脊髓免疫调节在AS慢性治疗中更为突出。因此，硝酰基通过减少脊髓神经胶质细胞活化来限制CCI诱导的神经性疼痛。
Chronic pain is a major health problem worldwide. We have recently demonstrated the analgesic effect of the nitroxyl donor, Angeli’s salt (AS) in models of inflammatory pain. In the present study, the acute and chronic analgesic effects of AS was investigated in chronic constriction injury of the sciatic nerve (CCI)-induced neuropathic pain in mice. Acute (7th day after CCI) AS treatment (1 and 3 mg/kg; s.c.) reduced CCI-induced mechanical, but not thermal hyperalgesia. The acute analgesic effect of AS was prevented by treatment with 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor), KT5823 (an inhibitor of protein kinase G [PKG]) or glibenclamide (GLB, an ATP-sensitive potassium channel blocker). Chronic (7–14 days after CCI) treatment with AS (3 mg/kg, s.c.) promoted a sustained reduction of CCI-induced mechanical and thermal hyperalgesia. Acute AS treatment reduced CCI-induced spinal cord allograft inflammatory factor 1 (known as Iba-1), interleukin-1β (IL-1β), and ST2 receptor mRNA expression. Chronic AS treatment reduced CCI-induced spinal cord glial fibrillary acidic protein (GFAP), Iba-1, IL-1β, tumor necrosis factor-α (TNF-α), interleukin-33 (IL-33) and ST2 mRNA expression. Chronic treatment with AS (3 mg/kg, s.c.) did not alter aspartate aminotransferase, alanine aminotransferase, urea or creatinine plasma levels. Together, these results suggest that the acute analgesic effect of AS depends on activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Moreover, chronic AS diminishes CCI-induced mechanical and thermal hyperalgesia by reducing the activation of spinal cord microglia and astrocytes, decreasing TNF-α, IL-1β and IL-33 cytokines expression. This spinal cord immune modulation was more prominent in the chronic treatment with AS. Thus, nitroxyl limits CCI-induced neuropathic pain by reducing spinal cord glial cells activation.