Issue Archive

N~(#omega#)--nitro--L--arginine methyl ester inhibits the up--regulated expression of neuronal nitric oxide synthase/NMDA receptor in the morphine analgesia tolerance rats

Yu Ling, Xue Fushan, Li Chengwen, Xu Yachao, Zhang Guohua, Liu Kunpeng, Liu Yi, Sun Haitao

Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences.Beijing 100041

Abstract

The effect of systemic administration of nonspecific nitric oxide synthase inhibitor （N~(#omega#)-nitro-L-arginine methyl ester, L-NAME） on morphine analgesia tolerance was observed by using the thermal tail-flick method, and the roles of NO and NMDA receptors in morphine analgesia tolerance were evaluated on the basis of the expressions of nNOS mRNA, NR_(1A) mRNA and NR_(2A) mRNA in spinal cord and midbrain. Thirty-six healthy adult Sprague-Dawley rats were randomly divided into six groups （6 rats per group）. Group 1, control group, received a subcutaneous （s.c.） injection of normal saline （1 ml）; Groups 2, 3, 4, 5 and 6, the treatment groups received s.c. injection of L-NAME 10 mg/kg, L-NAME 20 mg/kg, morphine 10 mg/kg, L-NAME 10 mg/kg + morphine 10 mg/kg, and L-NAME 20 mg/kg + morphine 10 mg/kg, respectively. All rats received s.c. injections twice per day （8:00 and 17:00）. The tail-flick latency （TFL） was measured in each rat before the injection as a baseline value, and then TFL at 50 min after the 1st injection every day as the measuring values. The animals （except for groups 2 and 5） were decapitated at 80 min after the last injection on the 8th day. The spinal segments and midbrain were removed for analysis of nNOS mRNA, NR_(1A) mRNA and NR_(2A) mRNA expressions by the RT-PCR method. The results showed that TFL remained unchangeable in group 2 compared with baseline value during the 7-day observation, while increased significantly on the 7th day in group 3. In group 4, TFL was longest on the 1st day, then decreased gradually from the 2rid day to the 6th day, and restored to the baseline value on the 6th day. In group 5, TFL showed a decreasing tendency during the 7-day observation, but was still significantly longer than the baseline value on the 7th day. The changes of TFL obtained in group 6 were similar to those in group 5. The results of RT-PCR showed that as compared with group 1, nNOS mRNA expressions in spinal cord and midbrain were significantly down-regulated in group 3, but the expressions of the NR_(1A) mRNA and NR_(2A) mRNA in both groups were similar, while the nNOS mRNA, NR_(1A) mRNA and NR_(2A) mRNA expressions were all significantly up-regulated in group 4. As compared with group 4, the expressions of nNOS mRNA, NR_(1A) mRNA and NR_(2A) mRNA were significantly inhibited in group 6. These results suggest that the expressions of nNOS and NMDA receptors in spinal cord and midbrain were significantly up-regulated in the rats with morphine analgesia tolerance. Chronic co-administration of L-NAME could effectively inhibit the morphine-induced overexpressions of nNOS and NMDA receptors, and postpone the development of morphine analgesia tolerance. Based on the results of this study, it is concluded that NO/NMDA receptor in spinal cord and midbrain is closely related to the development of morphine analgesia tolerance.

Key words: Morphine;analgesia tolerance;nitric oxide synthase;NMDA receptor

Received: 　　Accepted:

Corresponding author: 　　E-mail:

Citing This Article：

Yu Ling, Xue Fushan, Li Chengwen, Xu Yachao, Zhang Guohua, Liu Kunpeng, Liu Yi, Sun Haitao. N~(#omega#)--nitro--L--arginine methyl ester inhibits the up--regulated expression of neuronal nitric oxide synthase/NMDA receptor in the morphine analgesia tolerance rats. Acta Physiol Sin 2006; 58 (6): (in Chinese with English abstract).