Sophora alopecuroides L. var. alopecuroides alleviates morphine withdrawal syndrome in mice: involvement of alkaloid fraction and matrine

Document Type : Original Article


1 Research Institute for Islamic and Complementary Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran


Objective(s): Evaluation of the Sophora alopecuroides var. alopecuroides seed effects on morphine withdrawal syndrome in mice and determination of the alkaloid composition of the seed total extract.
Materials and Methods:The effects of the seed total extract, alkaloid fraction and major compound matrine on the mice morphine withdrawal syndrome were compared to saline and methadone.Mice were made dependent on morphine by morphine sulfate injection 3 times a day for 3 days. The withdrawal jumping and diarrhea were induced by administration of naloxone 2 hr after the 10th injection of morphine sulfate on the day 4. The total extract (100, 200, 300 mg/kg), alkaloid fraction (5, 10, 20 mg/kg), matrine (5, 15, 30 mg/kg), methadone (10 mg/kg) or saline were injected 30 min before naloxone. All drugs were administered by subcutaneous injection. The total extract alkaloid composition was also determined by gas chromatography (GC) and GC-MS analysis.
Results:All doses of the total extract, alkaloid fraction andmatrine as well as methadonedecreased jumping and diarrhea significantly compared to the saline. The effects of the total extract and alkaloid fraction were not significantly different from methadone. But, there were significant differences between the effects of matrine and methadone. Matrine, cytisine, sophoridine, n-methyl cytisine, sophocarpine and sophoramine were the major alkaloids. There was no nicotine in the total extract. 
Conclusion:S. alopecuroidesvar. alopecuroides suppresses opioid withdrawal with efficacy comparable to methadone. Matrine may be one of the alkaloids responsible for the effect of the plant.


1.Klein JW. Pharmacotherapy for substance use disorders. Med Clin North Am 2016; 100: 891-910. 
2. Bell J.Pharmacological maintenance treatments of opiate addiction. Br J Clin Pharmacol 2014; 77:253-263.
3. Diaper AM, Law FD, Melichar JK. Pharmacological strategies for detoxification. Br J Clin Pharmacol 2014; 77:302-314.
4. Reed K, Day E, Keen J, Strang J.Pharmacological treatments for drug misuse and dependence. Expert Opin Pharmacother 2015; 16:325-333.
5. Bailey CP, Husbands SM. Novel approaches for the treatment of psychostimulant and opioid abuse - focus on opioid receptor-based therapies. Expert Opin Drug Discov 2014; 9:1333-1344.
6. Tzschentke TM. Where do we stand in the field of anti-abuse drug discovery? Expert Opin Drug Discov 2014; 9:1255-1258.
7. Ward J, Rosenbaum C, Hernon C, McCurdy CR, Boyer EW. Herbal medicines for the management of opioid addiction: safe and effective alternatives to conventional pharmacotherapy? CNS Drugs 2011; 25:999-1007.
8. Tabatabai SM, Dashti S, Doosti F, Hosseinzadeh H. Phytotherapy of opioid dependence and withdrawal syndrome: a review. Phytother Res 2014; 28:811-830.
9. Mozaffarian V. Identification of medicinal and aromatic plants of Iran. Farhang Moaser. Iran 2013, p: 850.
10. Lu X, Lin B, Tang JG, Cao Z, Hu Y.Study on the inhibitory effect of total alkaliods of Sophora alopecuroides on osteosarcoma cell growth. Afr J Tradit Complement Altern Med 2014; 11:172-175.
11. Chang A, Cai Z, Wang Z, Sun S. Extraction and isolation of alkaloids of Sophora alopecuroides and their anti-tumor effects in H22 tumor-bearing mice. Afr J Tradit Complement Altern Med 2014; 11:245-248.
12. Leaviss J, Sullivan W, Ren S, Everson-Hock E, Stevenson M, Stevens JW, et al. What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. Health Technol Assess 2014; 18:1-120.
13. Cheng H, Xia B, Zhang L, Zhou F, Zhang YX, Ye M et al. Matrine improves 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice. Pharmacol Res 2006; 53:202-208.
14. Qiu S, Sun H, Zhang AH, Xu HY, Yan GL, Han Y et al. Natural alkaloids: basic aspects, biological roles, and future perspectives. Chin J Nat Med 2014; 12:401-406.
15. Zhang WL, Zhu L, Jiang JG. Active ingredients from natural botanicals in the treatment of obesity. Obes Rev 2014; 15:957-967.
16. Zhang XL, Xu HR, Chen WL, Chu NN, Li XN, Liu GY et al. Matrine determination and pharmacokinetics in human plasma using LC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:3253-3256.
17. Kianbakht S, Hajiaghaee R. Effects of Sophora alopecuroides L., Zingiber officinale Rosc. and Melissa officinalis L. in formalin and straub tail tests. J Med Plants 2014; 13:33-40.
18. Kamada H, Okamura N, Satake M, Harada H, Shimomura K. Alkaloid production by hairy root cultures in Atropa belladonna. Plant Cell Rep 1986; 5:239-242.
19. Adams RP. Identification of Essential Oil Components by Gas Chromatography/Quadrupole Mass Spectrometry. 4th ed. Allured Publishing Corporation. USA 2007, pp: 1-8.
20. Wu YJ, Chen JJ, Cheng YY. Determination of sophocarpine, matrine, and sophoridine in KUHUANG injection by GC-MS. J Anal Chem 2005; 60:967-973.
21. Kite GC, Pennington RT. Quinolizidine alkaloid status of Styphnolobium and Cladrastis (Leguminosae). Biochem Syst Ecol 2003; 31:1409-1416.
22. Lee ST, Cook D, Molyneux RJ, Marcolongo-Pereira C, Stonecipher CA, Gardner DR. The alkaloid profiles of Sophora nuttalliana and Sophora stenophylla. Biochem Syst Ecol 2013; 48: 58-64.
23. Zarrindast MR, Mohajeri S. Influence of ATP-dependent K+ channels on nicotine-induced inhibition of withdrawal in morphine-dependent mice. Eur J Pharmacol 2006 ; 552:90-98.
24. Zhang L, Li G, Houghton PJ, Jackson S, Twentyman PR. Alkaloids in Sophora alopecuroides seed and relevant tests for activity. Zhongguo Zhong Yao Za Zhi 1997; 22:740-743.
25. Schmeller T, Sauerwein M, Sporer F, Wink M, Muller WE. Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors. J Nat Prod 1994; 57:1316-1319.
26. Boido CC, Tasso B, Boido V, Sparatore F. Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities. Farmaco 2003; 58:265-277.
27. Rahman S, Engleman EA, Bell RL. Nicotinic receptor modulation to treat alcohol and drug dependence. Front Neurosci 2015; 8:426.
28. Zarrindast MR, Farzin D.Nicotine attenuates naloxone-induced jumping behaviour in morphine-dependent mice. Eur J Pharmacol 1996; 298:1-6.
29. Kamei J, Xiao P, Ohsawa M, Kubo H, Higashiyama K, Takahashi H et al. Antinociceptive effects of (+)-matrine in mice. Eur J Pharmacol 1997; 337:223-226.
30. Xiao P, Kubo H, Ohsawa M, Higashiyama K, Nagase H, Yan YN, et al. kappa-Opioid receptor-mediated antinociceptive effects of stereoisomers and derivatives of (+)-matrine in mice. Planta Med 1999; 65:230-233.
31. Higashiyama K, Takeuchi Y, Yamauchi T, Imai S, Kamei J, Yajima Y, et al. Implication of the descending dynorphinergic neuron projecting to the spinal cord in the (+)-matrine- and (+)-allomatrine-induced antinociceptive effects. Biol Pharm Bull 2005; 28:845-848.
32. Yin LL, Zhu XZ. The involvement of central cholinergic system in (+)-matrine-induced antinociception in mice. Pharmacol Biochem Behav 2005; 80:419-425.