Highfield D A, Grant S
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, USA.
Synapse. 1998 Jul;29(3):233-9. doi: 10.1002/(SICI)1098-2396(199807)29:3<233::AID-SYN5>3.0.CO;2-7.
Ng-nitro-L-arginine (L-NArg), a potent nitric oxide synthase inhibitor, has been implicated as a potential mechanism for attenuating the development of tolerance to opioid drugs and for suppressing opioid withdrawal. Neurons in the locus coeruleus (LC) express opioid receptors and these neurons exhibit both tolerance to chronic administration of opioids and antagonist-precipitated withdrawal hyperactivity. This study tested the hypothesis that L-NArg would attenuate the development of opioid tolerance in LC neurons. Challenge doses of morphine were administered while recording single-cell extracellular activity in brain slices from rats who had been concurrently treated for 5 days with morphine (75 mg morphine sulfate base pellets) and L-NArg (10 mg/kg, i.p., bid). The average ED50 for morphine of cells from rats who received L-NArg injections and morphine pellets was similar to that in cells from rats who had been implanted with sham pellets (14.5-18 nM). In contrast, the average ED50 of cells from morphine pelleted animals who received saline injections was substantially higher (34.5 nM). These results demonstrate that L-NArg attenuates the development of tolerance to morphine in LC neurons.
N-硝基-L-精氨酸（L-NArg）是一种强效的一氧化氮合酶抑制剂，被认为是减轻对阿片类药物耐受性发展以及抑制阿片类药物戒断反应的潜在机制。蓝斑（LC）中的神经元表达阿片受体，并且这些神经元对慢性给予阿片类药物表现出耐受性，同时对拮抗剂诱发的戒断性多动也有反应。本研究检验了L-NArg会减弱LC神经元中阿片类药物耐受性发展这一假说。在记录来自同时接受吗啡（75mg硫酸吗啡碱丸剂）和L-NArg（10mg/kg，腹腔注射，每日两次）治疗5天的大鼠脑片单细胞细胞外活动时，给予挑战剂量的吗啡。接受L-NArg注射和吗啡丸剂的大鼠细胞对吗啡的平均半数有效剂量（ED50）与接受假丸剂植入的大鼠细胞相似（14.5 - 18nM）。相比之下，接受盐水注射的吗啡丸剂动物细胞的平均ED50显著更高（34.5nM）。这些结果表明，L-NArg减弱了LC神经元对吗啡耐受性的发展。
