Morales Francisco, Constandil Luis, Pelissier Teresa, Hernández Alejandro, Laurido Claudio
Arthritis Res Ther. 2012 Aug 24;14(4):R196. doi: 10.1186/ar4030.
Multiple studies have shown that glial cells of the spinal cord, such as astrocytes and microglia, have close contact with neurons, suggesting the term tripartite synapse. In these synapses, astrocytes surrounding neurons contribute to neuronal excitability and synaptic transmission, thereby increasing nociception and thus the persistence of chronic pain. Conversely, the N-methyl-D-aspartate (NMDA) receptor is crucial in the generation and maintenance of chronic pain. It has multiple sites of modulation. One is the site of recognition of extracellular neurotransmitter (glutamate), which can be blocked by competitive antagonists such as (3-(2-carboxipiperazin-4)1-propyl phosphonic acid), (±)-CPP, resulting in a blockade of the calcium current and thus the intracellular transduction process. In the present study, we investigated whether the potential antinociceptive effect of glial inhibition produced by propentofylline (PPF) can be enhanced when combined with an NMDA-receptor inhibitor such as (±)-CPP.
We used Sprague-Dawley monoarthritic rats. The monoarthritis was induced by injection of complete Freund adjuvant in the right tibiotarsal joint. Four weeks later, rats were treated with PPF (1, 10, 30, and 100 μg/10 μl) intrathecally (i.t.) for 10 days, injected once with (±)-CPP (2.5, 5, 12.5, 25, 50, and 100 μg/10 μl, i.t.), or both treatments combined. The antinociceptive effect was evaluated on day 11 for PPF and immediately to (±)-CPP, by assessing the vocalization threshold to mechanical stimulation of the arthritic paw.
The data indicate that intrathecal administration of increasing concentrations of (±)-CPP or PPF produced a significant dose-dependent antinociceptive effect with respect to monoarthritic rats receiving saline. The linear regression analysis showed that the dose that produces 30% of maximal effect (ED₃₀) for i.t. (±)-CPP was 3.97 μg, and 1.42 μg for i.t. PPF. The administration of the PPF and (±)-CPP combination in fixed proportions of ED₃₀ produced a dose-dependent antinociceptive effect, showing an interaction of the supraadditive type.
The results suggest that glia inhibitors can synergically potentiate the effect of glutamate blockers for the treatment of chronic inflammatory pain.
多项研究表明，脊髓中的胶质细胞，如星形胶质细胞和小胶质细胞，与神经元密切接触，由此提出了三方突触这一术语。在这些突触中，围绕神经元的星形胶质细胞有助于神经元的兴奋性和突触传递，从而增加伤害感受，进而导致慢性疼痛的持续存在。相反，N-甲基-D-天冬氨酸（NMDA）受体在慢性疼痛的产生和维持中起关键作用。它有多个调节位点。其中一个是细胞外神经递质（谷氨酸）的识别位点，可被竞争性拮抗剂如（3-(2-羧基哌嗪-4)-1-丙基膦酸），（±）-CPP阻断，从而阻断钙电流，进而阻断细胞内转导过程。在本研究中，我们调查了丙戊茶碱（PPF）产生的胶质抑制潜在的抗伤害感受作用与NMDA受体抑制剂如（±）-CPP联合使用时是否能增强。
我们使用了Sprague-Dawley单关节炎大鼠。通过在右胫跗关节注射完全弗氏佐剂诱导单关节炎。四周后，大鼠鞘内注射PPF（1、10、30和100μg/10μl），持续10天，单次注射（±）-CPP（2.5、5、12.5、25、50和100μg/10μl，鞘内注射），或两种治疗联合使用。在第11天评估PPF产生抗伤害感受作用的情况，对于（±）-CPP则在注射后立即评估，通过评估对关节炎爪子机械刺激的发声阈值来进行。
数据表明，对于接受生理盐水的单关节炎大鼠，鞘内注射浓度递增的（±）-CPP或PPF产生了显著的剂量依赖性抗伤害感受作用。线性回归分析表明，鞘内注射（±）-CPP产生最大效应的30%（ED₃₀）的剂量为3.97μg，鞘内注射PPF的剂量为1.42μg。以ED₃₀的固定比例联合使用PPF和（±）-CPP产生了剂量依赖性抗伤害感受作用，显示出超相加类型的相互作用。
结果表明，胶质抑制剂可协同增强谷氨酸阻滞剂治疗慢性炎症性疼痛的效果。
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