Abdel-Zaher Ahmed O, Hamdy Moustafa M, Aly Saida A, Abdel-Hady Randa H, Abdel-Rahman Samy
Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Eur J Pharmacol. 2006 Jul 1;540(1-3):60-6. doi: 10.1016/j.ejphar.2006.03.059. Epub 2006 Apr 1.
The effect of aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, on morphine-induced tolerance and dependence in mice was investigated in this study. Acute administration of aminoguanidine (20 mg/kg, p.o.) did not affect the antinociceptive effect of morphine (10 mg/kg, s.c.) as measured by the hot plate test. Repeated administration of aminoguanidine along with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. Also, the development of morphine dependence as assessed by naloxone-precipitated withdrawal manifestations was reduced by co-administration of aminoguanidine. The effect of aminoguanidine on naloxone-precipitated withdrawal was enhanced by concurrent administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (0.25 mg/kg, i.p.) or the non-specific nitric oxide synthase (NOS) inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME; 5 mg/kg, i.p.) and antagonized by concurrent administration of the nitric oxide (NO) precursor, l-arginine (50 mg/kg, p.o.). Concomitantly, the progressive increase in NO production, but not in brain glutamate level, induced by morphine was inhibited by repeated administration of aminoguanidine along with morphine. Similarly, co-administration of aminoguanidine inhibited naloxone-induced NO overproduction, but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The effect of aminoguanidine on naloxone-induced NO overproduction was potentiated by concurrent administration of dizocilpine or l-NAME and antagonized by concurrent administration of l-arginine. These results provide evidence that blockade of NO overproduction, the consequence of NMDA receptor activation, by aminoguanidine, via inhibition of iNOS, can attenuate the development of morphine tolerance and dependence.
本研究探讨了诱导型一氧化氮合酶（iNOS）抑制剂氨基胍对小鼠吗啡诱导的耐受性和依赖性的影响。通过热板试验测定，急性给予氨基胍（20mg/kg，口服）不影响吗啡（10mg/kg，皮下注射）的镇痛作用。氨基胍与吗啡重复给药可减弱对吗啡镇痛作用耐受性的发展。此外，通过纳洛酮诱发的戒断表现评估，氨基胍与吗啡联合给药可减轻吗啡依赖性的发展。同时给予非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂地佐环平（0.25mg/kg，腹腔注射）或非特异性一氧化氮合酶（NOS）抑制剂L-N(G)-硝基精氨酸甲酯（L-NAME；5mg/kg，腹腔注射）可增强氨基胍对纳洛酮诱发戒断的作用，而同时给予一氧化氮（NO）前体L-精氨酸（50mg/kg，口服）则可拮抗该作用。同时，氨基胍与吗啡重复给药可抑制吗啡诱导的NO生成的逐渐增加，但不影响脑谷氨酸水平。同样，氨基胍与吗啡联合给药可抑制纳洛酮诱导的NO过量生成，但不抑制纳洛酮诱导的吗啡依赖小鼠脑谷氨酸水平的升高。地佐环平或L-NAME同时给药可增强氨基胍对纳洛酮诱导的NO过量生成的作用，而L-精氨酸同时给药则可拮抗该作用。这些结果表明，氨基胍通过抑制iNOS阻断NMDA受体激活导致的NO过量生成，可减轻吗啡耐受性和依赖性的发展。
