Study the Effect and Mechanism of Dextromethorphan on Preventing the Development of Morphine Tolerance and Dependence in Rats

Shiou-Lan Chan ； Chang-Chih Chou ； Chih-Shung Wong ； Chin-Chen Wu ； Pao-Luh Tao

《Journal of Medical Sciences》 22卷4期 (2002/08) Pp. 171-176

並列摘要

Objectives: To investigate the effects of dextromethorphan (DM) on preventing the development of morphine tolerance and dependence and the role of glutamate release, NMDA receptor and nitric oxide (NO) in this process. Methods: Male Sprague-Dawley rats (300-350 gm) were treated s.c. with either saline or morphine (escalating doses: 5-65 mg/kg) or morphine+DM (20 mg/kg) twice daily for 7 days. Antinociceptive effect was assessed by tailflick test and up-down method before and after treatment (day 0, 3, 5 and 7). Spinal cord slices (450 μm) were prepared 30 min after drug treatment on day 8 and [³H] glutamate and NO released were determined. Results: We found that pretreatment with DM decreased the degree of tolerance that induced by morphine and also partially suppressed the precipitated withdrawal syndromes. The percentage of in vitro spinal release of [³H] glutamate by 100μM morphine was the same in 3 groups. The affinity of NMDA receptors of spinal cord was increased but the B [93d0] was decreased after chronic morphine or chronic (morphine + DM) treatment. The basal NO level in the spinal cord slices preparation was increased in chronic morphine treatment group but not in the group of chronic (morphine + DM). Adding 100μM morphine in the medium of spinal cord slices also increased NO release in each group. However this effect was suppressed by MK-801 (100μM) only in the control group. Conclusions: Dextromethorphan can prevent the development of morphine tolerance and dependence in rats. The mechanism may be due to the property of DM to block the NMDA receptors and NO synthesis.

並列關鍵字

dependence ； dextromethorphan ； morphine ； NMDA receptor ； tolerance