Drug Res (Stuttg) 2018; 68(01): 33-37
DOI: 10.1055/s-0043-116948
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats

Hamed Ghavimi
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zanjan University of Medical Science, Zanjan, Iran
Sara Darvishi
Student Research Committee, Zanjan University of Medical Science, Zanjan, Iran
Saeed Ghanbarzadeh
Zanjan Pharmaceutical Nanotechnology Research Center, and Department of Pharmaceutics, Faculty of Pharmacy, Zanjan University of Medical Science, Zanjan, Iran
› Author Affiliations
Further Information

Publication History

received 12 January 2017

accepted 18 July 2017

Publication Date:
28 August 2017 (eFirst)


Background Dependence and tolerance to morphine are major problems which limit its chronic clinical application.

Purpose This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance.

Methods Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5–25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated.

Results Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively).

Conclusion In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence.