Pasternak G W, Kolesnikov Y A, Babey A M
Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Neuropsychopharmacology. 1995 Dec;13(4):309-13. doi: 10.1016/0893-133X(95)00084-Q.
Opioid tolerance can be modulated by the N-methyl-D-aspartate/nitric oxide (NMDA/NO) cascade. Evidence exploring a daily injection paradigm indicates that agents antagonizing NMDA receptors can prevent tolerance to morphine and delta drugs, but not kappa agents. Drugs work regardless of whether they act as competitive or noncompetitive antagonists. Even an agent acting as an antagonist on the glycine site of the NMDA receptor is effective. Blockade of nitric oxide synthase has similar effects on opioid tolerance, preventing morphine and delta tolerance but not that of kappa drugs. Even methylene blue, which can inhibit guanylyl cyclase activity, is effective, presumably by blocking cGMP formation resulting from NO release. These results demonstrate the importance of an intact NMDA/NO cascade in the production of opioid tolerance and open new possibilities in the design of agents acting on opioid tolerance.
阿片类药物耐受性可通过N-甲基-D-天冬氨酸/一氧化氮（NMDA/NO）级联反应进行调节。探索每日注射模式的证据表明，拮抗NMDA受体的药物可预防对吗啡和δ类药物的耐受性，但对κ类药物无效。无论药物是作为竞争性还是非竞争性拮抗剂起作用，均有效果。即使是在NMDA受体甘氨酸位点起拮抗剂作用的药物也有效。一氧化氮合酶的阻断对阿片类药物耐受性有类似作用，可预防吗啡和δ类药物耐受性，但对κ类药物无效。即使是可抑制鸟苷酸环化酶活性的亚甲蓝也有效，可能是通过阻断由NO释放导致的cGMP形成。这些结果证明了完整的NMDA/NO级联反应在阿片类药物耐受性产生中的重要性，并为设计作用于阿片类药物耐受性的药物开辟了新的可能性。
