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首页> 外文期刊>Anesthesia and Analgesia: Journal of the International Anesthesia Research Society >Topical combinations to treat microvascular dysfunction of chronic postischemia pain
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Topical combinations to treat microvascular dysfunction of chronic postischemia pain

机译：局部用药治疗慢性缺血后疼痛的微血管功能障碍

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BACKGROUND: Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. METHODS: Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. RESULTS: Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56). CONCLUSIONS: The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.
机译：背景：越来越多的证据表明，患有复杂区域疼痛综合征（CRPS）的患者表现出由皮肤，肌肉和神经血管微血管功能障碍引起的组织异常。我们测试了旨在改善微血管功能的局部用药组合能否缓解CRPS动物模型中的异常性疼痛。我们假设局部给予α2-肾上腺素能（α2A）受体激动剂或一氧化氮（NO）供体以增加动脉血流量，再结合磷脂酸（PA）或磷酸二酯酶（PDE）抑制剂可增加毛细血管血流量。有效减轻慢性疼痛动物模型中的异常性疼痛和微血管功能障碍的体征。方法：机械性异常性疼痛是在慢性缺血后疼痛（CPIP）大鼠的后爪中诱发的。在局部应用赋形剂，单一药物或α2A受体激动剂（阿普拉可尼定）或NO供体（林西多明）与PA或PDE抑制剂（利索茶碱，己酮可可碱）组合使用前后，评估痛觉异常。还评估了阿帕可乐定+莱索茶碱的局部组合对CPIP大鼠微血管功能（闭塞后反应性充血）和组织氧化能力（四氮唑还原产生的甲a生成）的影响。结果：在CPIP大鼠中，每种单一局部用药与媒介物相比均产生显着的剂量依赖性抗痛觉过敏作用（N = 30），并且PA或PDE抑制剂的抗痛觉过敏剂量反应曲线均是5至10倍。当与非止痛剂量的α2A受体激动剂或NO供体联合使用时（N = 28）。对侧后爪的相同治疗未重现同侧α2A受体激动剂或NO供体与PA或PDE抑制剂联合治疗的抗痛觉过敏作用（N = 28）。局部用药产生的抗痛觉过敏作用可持续长达6小时（N = 15），并且在CPIP大鼠早期（而非晚期）（N = 18）被低剂量全身普瑞巴林显着增强。还发现一种抗痛觉过敏的局部用阿普可乐定+赖索茶碱组合可以有效缓解CPIP大鼠抑郁的闭塞性反应后充血（N = 61），并增加缺血后组织（皮肤和肌肉）的甲maz生成（N = 56）。结论：本研究结果支持以下假设：通过α2A受体激动剂或NO供体与PA或PDE抑制剂的局部组合可有效缓解CRPS动物模型中的异常性疼痛。这表明旨在通过增加动脉和毛细血管血流量来改善微血管功能的局部治疗可产生有效的CRPS镇痛。

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