Astrocyte D-serine modulates the activation of neuronal NOS leading to the development of mechanical allodynia in peripheral neuropathy
Astrocyte D-serine modulates the activation of neuronal NOS leading to the development of mechanical allodynia in peripheral neuropathy
复制标题
DOI：
10.1177/1744806919843046
复制
发表时间：
2019-04-01
期刊：
影响因子：
3.3
通讯作者：
Lee, Jang-Hern
中科院分区：
文献类型：
--
作者：
Choi, Sheu-Ran;Roh, Dae-Hyun;Lee, Jang-Hern
脊髓D-丝氨酸通过增加N-甲基-D-天冬氨酸（NMDA）受体GluN 1亚基（pGluN 1）的磷酸化在伤害感受中起重要作用。然而，这一过程的细胞机制尚未阐明。在这里，我们研究了神经元型一氧化氮合酶（nNOS）在D-丝氨酸诱导的NMDA受体功能增强和慢性压迫性损伤（CCI）模型中神经病理性疼痛的诱导中的可能作用。在术后0-3天鞘内给予丝氨酸消旋酶抑制剂L-丝氨酸O-硫酸钾盐（LSOS）或D-丝氨酸降解酶D-氨基酸氧化酶（DAAO）显著降低了CCI诱导的一氧化氮（NO）水平的增加和腰背角神经元中的烟酰胺腺嘌呤二核苷酸磷酸-黄递酶染色，以及CCI手术后第3天CCI诱导的nNOS（pnNOS）磷酸化（Ser 847）减少。在术后第3天，LSOS或DAAO给药抑制了CCI诱导的机械性异常性疼痛和GluN 1的蛋白激酶C（PKC）依赖性（Ser 896）磷酸化的发生，这被NO供体3-吗啉代酮亚胺盐酸盐（SIN-1）的共同给药逆转。在幼稚小鼠中，外源性D-丝氨酸通过减少pnNOS增加NO水平。D-丝氨酸诱导的机械超敏反应，NO水平，PKC依赖性pGluN 1，和NMDA诱导的自发伤害性感受的增加减少预处理与nNOS抑制剂，7-硝基吲唑或与NMDA受体拮抗剂，7-氯犬尿烯酸和MK-801。总的来说，我们发现脊髓D-丝氨酸调节nNOS活性和伴随的NO产生，导致PKC依赖性pGluN 1增加，并最终导致周围神经损伤后机械性异常性疼痛的诱导。
Spinal D-serine plays an important role in nociception via an increase in phosphorylation of the N-Methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). However, the cellular mechanisms underlying this process have not been elucidated. Here, we investigate the possible role of neuronal nitric oxide synthase (nNOS) in the D-serine-induced potentiation of NMDA receptor function and the induction of neuropathic pain in a chronic constriction injury (CCI) model. Intrathecal administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt (LSOS) or the D-serine degrading enzyme, D-amino acid oxidase (DAAO) on post-operative days 0-3 significantly reduced the CCI-induced increase in nitric oxide (NO) levels and nicotinamide adenine dinucleotide phosphate-diaphorase staining in lumbar dorsal horn neurons, as well as the CCI-induced decrease in phosphorylation (Ser847) of nNOS (pnNOS) on day 3 post-CCI surgery. LSOS or DAAO administration suppressed the CCI-induced development of mechanical allodynia and protein kinase C (PKC)-dependent (Ser896) phosphorylation of GluN1 on day 3 post-surgery, which were reversed by the co-administration of the NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1). In naive mice, exogenous D-serine increased NO levels via decreases in pnNOS. D-serine-induced increases in mechanical hypersensitivity, NO levels, PKC-dependent pGluN1, and NMDA-induced spontaneous nociception were reduced by pretreatment with the nNOS inhibitor, 7-nitroindazole or with the NMDA receptor antagonists, 7-chlorokynurenic acid and MK-801. Collectively, we show that spinal D-serine modulates nNOS activity and concomitant NO production leading to increases in PKC-dependent pGluN1 and ultimately contributing to the induction of mechanical allodynia following peripheral nerve injury.