From the *Alan Edwards Centre for Research on Pain, Department of Anesthesia, †Department of Psychology, ‡Alan Edwards Centre for Research on Pain, Department of Anesthesia, Neurology and Neurosurgery, and Psychology, and §Anesthesia Research Unit, McGill University Health Centre Research Institute, Montreal, QC, Canada.
Anesth Analg. 2014 Apr;118(4):830-40. doi: 10.1213/ANE.0000000000000141.
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.
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.
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).
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.
越来越多的证据表明，患有复杂性区域疼痛综合征 (CRPS) 的患者表现出由皮肤、肌肉和神经血管的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联合用药是否会缓解 CRPS 动物模型中的痛觉过敏。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，联合使用磷脂酸 (PA) 或磷酸二酯酶 (PDE) 抑制剂以增加毛细血管血流量，将有效减轻慢性疼痛动物模型中的痛觉过敏和微血管功能障碍的迹象。
在慢性缺血后疼痛 (CPIP) 的大鼠后爪中诱导机械性痛觉过敏。在局部应用载体、单一药物或 α2A 受体激动剂 (阿可乐定) 或 NO 供体 (利辛胺) 与 PA 或 PDE 抑制剂 (利福喷丁、己酮可可碱) 的组合之前和之后，评估痛觉过敏。还评估了阿可乐定+利福喷丁的局部联合用药对 CPIP 大鼠微血管功能 (闭塞后反应性充血) 和组织氧化能力 (四唑还原形成甲臜) 的影响。
与 CPIP 大鼠中的载体相比，每种单一局部药物都产生了显著的剂量依赖性抗痛觉过敏作用 (N = 30)，并且当与非镇痛剂量的 α2A 受体激动剂或 NO 供体联合使用时，PA 或 PDE 抑制剂的抗痛觉过敏剂量反应曲线向左移动了 5-10 倍 (N = 28)。同侧用 α2A 受体激动剂或 NO 供体与 PA 或 PDE 抑制剂联合治疗产生的强烈抗痛觉过敏作用不能被对侧后爪的相同治疗复制 (N = 28)。局部联合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 大鼠的早期阶段，低剂量的全身普瑞巴林显著增强了这种作用，但在晚期阶段则没有 (N = 18)。还发现阿可乐定+利福喷丁的抗痛觉过敏局部联合用药也能有效缓解 CPIP 大鼠的闭塞后反应性充血降低 (N = 61)，并增加缺血组织 (皮肤和肌肉) 中的甲臜生成 (N = 56)。
本研究结果支持这样的假设，即 CRPS 动物模型中的痛觉过敏可通过局部联合使用α2A 受体激动剂或 NO 供体与 PA 或 PDE 抑制剂有效缓解。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为 CRPS 提供有效的镇痛作用。
