Sickle cell disease is the most common hemoglobinopathy and affects millions worldwide. The disease is associated with severe organ dysfunction, acute and chronic pain, and significantly decreased life expectancy. The large body of work demonstrating that hemolysis results in rapid consumption of the endogenous vasodilator nitric oxide, decreased nitric oxide production, and promotion of vaso-occlusion provides the basis for the hypothesis that nitric oxide bioavailability is reduced in sickle cell disease and that this deficit plays a role in sickle cell disease pain. Despite initial promising results, large clinical trials using strategies to increase nitric oxide bioavailability in sickle cell disease patients yielded no significant change in duration or frequency of acute pain crises. Further, recent investigations showed that sickle cell disease patients and mouse models have elevated baseline levels of blood nitrite, a reservoir for nitric oxide formation and a product of nitric oxide metabolism, regardless of pain phenotype. These conflicting results challenge the hypotheses that nitric oxide bioavailability is decreased and that it plays a significant role in the pathogenesis in sickle cell disease acute pain crises. Conversely, a large body of work demonstrates that nitric oxide, as a neurotransmitter, has a complex role in pain neurobiology, contributes to the development of central sensitization, and can mediate hyperalgesia in inflammatory and neuropathic pain. These results support an alternative hypothesis: one proposing that altered nitric oxide signaling may contribute to the development of neuropathic and/or inflammatory pain in sickle cell disease through its role as a neurotransmitter.

镰状细胞病是最常见的血红蛋白病，影响着全世界数百万人。该疾病与严重的器官功能障碍、急性和慢性疼痛以及预期寿命显着缩短有关。大量工作表明溶血导致内源性血管扩张剂一氧化氮快速消耗、一氧化氮产生减少和促进血管闭塞，为镰状细胞病中一氧化氮生物利用度降低以及这种缺陷的假设提供了基础在镰状细胞病疼痛中起作用。尽管最初取得了可喜的结果，但使用策略提高镰状细胞病患者一氧化氮生物利用度的大型临床试验并未对急性疼痛危机的持续时间或频率产生显着变化。更远，最近的研究表明，无论疼痛表型如何，镰状细胞病患者和小鼠模型的血亚硝酸盐基线水平升高，亚硝酸盐是一氧化氮形成的储存库和一氧化氮代谢的产物。这些相互矛盾的结果对一氧化氮生物利用度降低以及它在镰状细胞病急性疼痛危机的发病机制中起重要作用的假设提出了挑战。相反，大量工作表明，一氧化氮作为一种神经递质，在疼痛神经生物学中具有复杂的作用，有助于中枢敏化的发展，并可介导炎症和神经性疼痛中的痛觉过敏。这些结果支持另一种假设：