Department of Anesthesia, McGill University, Montreal, QC, Canada.
Department of Chemistry, McGill University, Montreal, QC, Canada.
J Neurochem. 2020 Mar;152(5):570-584. doi: 10.1111/jnc.14943. Epub 2020 Jan 27.
Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti-allodynic effect of a combination of two NO-modulating drugs: meldonium and N-acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post-ischemic pain (CPIP), a rat model of CRPS, as well as chronic constriction injury (CCI) of the sciatic nerve and chemotherapy-induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium-NAC produced significant anti-allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium-NAC produced an increase in the duration of anti-allodynia in the CPIP and CCI rats. While pre-treatment with an NO synthase inhibitor attenuated the anti-allodynic effects of meldonium-NAC, 30-min hyperbaric oxygen treatment combined with a non-effective dose of meldonium-NAC produced significant anti-allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti-allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium-NAC and revealed significantly increased plantar muscle NO levels in drug-treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia/hypoxia in these conditions, with emphasis on the role of NO.
局部微血管功能障碍和随之发生的组织缺血/缺氧导致复杂区域疼痛综合征 (CRPS) 和周围神经性疼痛的症状。由于一氧化氮 (NO) 是微血管血流的关键调节剂，因此增加其含量的化合物可能对这些疼痛状况具有治疗作用。这使我们假设局部组织 NO 水平调节药物的外用给药可以缓解 CRPS 和周围神经性疼痛的疼痛。我们研究了两种 NO 调节药物（ meldonium 和 N-乙酰半胱氨酸 (NAC)）组合的抗痛觉过敏作用。两种药物的等摩尔局部制剂在慢性缺血后疼痛 (CPIP) 、 CRPS 的大鼠模型以及坐骨神经慢性缩窄性损伤 (CCI) 和化疗引起的痛性神经病 (CIPN) 、周围神经性疼痛的大鼠模型上进行了测试。局部 meldonium-NAC 在 CPIP 、 CCI 和 CIPN 大鼠中产生了显著的抗痛觉过敏作用。此外，局部 meldonium-NAC 的重复应用增加了 CPIP 和 CCI 大鼠抗痛觉过敏的持续时间。虽然一氧化氮合酶抑制剂预处理减弱了 meldonium-NAC 的抗痛觉过敏作用，但 30 分钟高压氧处理与非有效剂量的 meldonium-NAC 联合使用在 CPIP 大鼠中产生了显著的抗痛觉过敏作用。这两项实验都表明一氧化氮参与了药物组合的抗痛觉过敏作用。为了确定局部组织 NO 变化所起的作用，我们在 CPIP 大鼠的足底进行了 meldonium-NAC 局部治疗后，对足底肌肉中的 NO 进行了定量，并显示出药物治疗组的足底肌肉中 NO 水平显著增加。该药物组合还逆转了 CPIP 后爪中通常观察到的组织氧合减少。除了为 CRPS 和周围神经性疼痛中的机械性痛觉过敏引入一种新的局部治疗方法外，这项工作还展示了针对这些疾病中微血管功能障碍和组织缺血/缺氧的局部靶向治疗的镇痛潜力，重点是一氧化氮的作用。
