Staunton C A, Barrett-Jolley R, Djouhri L, Thippeswamy T
Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Department of Physiology, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Exp Physiol. 2018 Apr 1;103(4):535-544. doi: 10.1113/EP086764. Epub 2018 Mar 7.
What is the central question of this study? Can modulation of inducible NO synthase reduce pain behaviour and pro-inflammatory cytokine signalling in a rat model of neuropathic pain? What is the main finding and its importance? Nitric oxide synthase-based therapies could be effective for the treatment of peripheral neuropathic pain.
Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7-8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg ) was administered i.p. at 8 h intervals for 3 days starting at 18 h post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme-linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post-SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)-1α, IL-1β and IL-10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP.
本研究的核心问题是什么？在神经性疼痛大鼠模型中，诱导型一氧化氮合酶的调节能否减轻疼痛行为和促炎细胞因子信号传导？主要发现及其重要性是什么？基于一氧化氮合酶的疗法可能对治疗周围神经性疼痛有效。
周围神经性疼痛（PNP）由周围神经损伤或功能障碍引起，是一个影响7% - 8%人口的主要健康问题。目前的药物对其控制不佳，其特征为疼痛超敏，这被认为是由于各种炎症介质使周围和中枢神经系统神经元致敏所致。在此，我们在PNP大鼠模型中研究：（i）使用诱导型一氧化氮合酶（iNOS）的高度选择性抑制剂1400W降低一氧化氮（NO）水平是否能预防或减轻疼痛超敏；以及（ii）1400W对慢性疼痛状态下iNOS上调后分泌的几种细胞因子血浆浓度的影响。采用PNP的L5脊神经切断术（SNA）模型，在SNA后18小时开始，以8小时的间隔腹腔注射1400W（20mg/kg），持续3天。使用多重酶联免疫吸附测定法检测用1400W处理的SNA大鼠血浆中12种细胞因子浓度的变化。SNA大鼠出现机械性和热超敏的行为体征。与载体/对照组相比，1400W显著：（i）限制了SNA后66小时机械性超敏的发展以及42小时和此后几个测试时间点热超敏的发展；（ii）增加了SNA大鼠血浆中白细胞介素（IL）-1α、IL-1β和IL-10的浓度。这些发现表明，1400W可能通过降低iNOS并改变促炎（IL-1β和IL-1α）和抗炎（IL-10）细胞因子之间的平衡发挥其镇痛作用，并且针对NO或其酶的疗法可能对治疗PNP有效。
