一氧化氮及一氧化氮合酶与吗啡耐受关系的新进展

疼痛治疗中长期给予吗啡易导致严重的耐受问题.多年来,针对耐受机制的研究表明NMDA/NO级联反应参与耐受的发生及发展.一氧化氮(nitric oxide,NO)主要是由一氧化氮合酶(nitric oxide synthase,NOS)催化其惟一前体--L-精氨酸生成NO和瓜氨酸.研究者们证实了大鼠鞘内吗啡耐受后脊髓内NOS尤其是nNOS的表达增高,耐受机制主要通过N-甲基-天门冬氨酸(N-methyL-D-aspartate,NMDA)受体的激活以及胞内钙离子浓度的升高来调节NOS的活性而触发NMDA/NO级联反应,继而影响耐受的发展.诸多研究给予吗啡的同时给予NOS抑制剂可以阻止耐受的发生,甚至在耐受形成后应用NOS抑制剂也可以翻转已经建立的耐受.但证实NOS各亚型在耐受中的具体作用仍不明确,需开展相关的研究进一步阐述其间的关系.

Research progress in interactions between nitric oxide, nitric oxide synthase and morphine tolerance

Chronic morphine which is commonly used to treat severe and chronic pain leads to analgesia tolerance. According to the research towards mechanism of tolerance, people demonstrated that NMDA/NO cascade might contribute to the development of morphine antinociceptive tolerance. NO is enzymatically formed from the unique precursor L-arginine by nitric oxide synthase. Expression of nitric oxide synthase, especially neuronal nitric oxide synthase, was found to be increased in the spinal cord of rat during the development of morphine antinociceptive tolerance. Activation of NMDA receptors and elevated level of intracellular calcium resulted in increased activities of nitric oxide synthase and stimulation of NMDA/NO cascade, in turn, exacerbated the development of tolerance. Coadministration of nitric oxide synthase inhibitor with morphine could prevent the development of tolerance to morphine-induced antinociception, even resulted in reversal of morphine antinociceptive tolerance, but the exact roles are still unclear. Additional studies need to be run to elucidate these in future.