Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Curitiba 81540-990, PR, Brazil.
Neuropharmacology. 2012 Dec;63(8):1286-97. doi: 10.1016/j.neuropharm.2012.08.009. Epub 2012 Sep 1.
Diabetes is often associated with painful neuropathy. The current treatments are symptomatic and ineffective. Cannabinoids have been proposed as promising drugs for chronic pain treatment and its antinociceptive effect has already been related in nerve injury models of neuropathic pain, but little has been investigated in painful diabetic neuropathy models. Thus, the current study aims to investigate the potential antinociceptive effect of drugs that alter endocannabinoid system when injected subcutaneously into the dorsal surface of the ipsilateral hind paw in chemical hyperalgesia induced by formalin in both normoglycemic (Ngl) and streptozotocin-diabetic (Dbt) rats. Diabetic rats exhibited exaggerated flinching behaviors during first and second phases of the formalin test, indicating the presence of hyperalgesia. AM404, an anandamide (AEA) re-uptake inhibitor, AEA (an agonist of CB1/CB2 receptors) or ACEA (a selective CB1 receptor agonist) induced antinociception in both phases of formalin test in Ngl and Dbt rats. In both groups, the antinociceptive effect of ACEA was prevented by AM251, a CB1 inverse agonist while the antinociceptive effect of AEA was prevented by AM251 or AM630, a CB2 receptor antagonist. In Ngl rats, the antinociceptive effect of AM404 was prevented by AM251 or capsazepine only during first phase of the formalin test while in Dbt rats, this effect was blocked by pretreatment with AM251 (both phases) or AM630 (second phase). Taken together, these results demonstrated broad-spectrum antinociceptive properties of cannabinoids in a model of painful diabetic neuropathy. Peripheral activation of both cannabinoid receptors seems to mediate the antinociceptive effect of exogenous or endogenous anandamide.
糖尿病常伴有疼痛性神经病变。目前的治疗方法是对症治疗，且无效。大麻素已被提议作为治疗慢性疼痛的有前途的药物，其抗伤害感受作用已在神经损伤性疼痛的神经病变模型中得到相关研究，但在痛性糖尿病神经病变模型中研究甚少。因此，本研究旨在探讨当皮下注射到正常血糖（Ngl）和链脲佐菌素糖尿病（Dbt）大鼠福尔马林诱导的化学性痛觉过敏的对侧后爪背表面时，改变内源性大麻素系统的药物的潜在镇痛作用。糖尿病大鼠在福尔马林测试的第一和第二阶段表现出明显的退缩行为，表明存在痛觉过敏。AM404，一种花生四烯酸（AEA）再摄取抑制剂，AEA（CB1/CB2 受体激动剂）或 ACEA（选择性 CB1 受体激动剂）在 Ngl 和 Dbt 大鼠的福尔马林测试的两个阶段均诱导出镇痛作用。在两组中，CB1 反向激动剂 AM251 可阻断 ACEA 的镇痛作用，而 CB2 受体拮抗剂 AM251 或 AM630 可阻断 AEA 的镇痛作用。在 Ngl 大鼠中，AM404 的镇痛作用仅在福尔马林测试的第一阶段被 AM251 或辣椒素阻断，而在 Dbt 大鼠中，这种作用被 AM251（两个阶段）或 AM630（第二阶段）预处理阻断。总之，这些结果表明大麻素在痛性糖尿病神经病变模型中具有广谱镇痛特性。外周激活两种大麻素受体似乎介导外源性或内源性花生四烯酸的镇痛作用。
