Effect of ethanolic extract of Safflower on naloxone-induced morphine withdrawal signs in mice

Document Type : Original Article


Dr. Saeid Abbasi -Maleki Room (No) 146, Department of Pharmacology, Faculty of Veterinary Medicine and Paramedical science, Urmia Branch, Islamic Azad University, 2 km Airport Road, Urmia, Iran.


Background and aims: Safflower (Carthamus tinctorius L.)from Asteraceae family has different biological activities including analgesic, antidepressant, anti-inflammatory, antispasmodic and neuroprotective effects. This study designed to evaluate its effect on naloxone -induced morphine withdrawal signs. Methods: In this experimental study, male NMRI mice (25-30 g) were randomly divided into 5 groups of 8: control groups received morphine and normal saline (10ml/kg) and other groups received fluoxetine (20mg/kg) and different doses of ethanolic extract of Safflower (100,200 and 400mg/kg).Morphine dependency was induced by intraperitoneal (i.p.) injection of increasing doses (50-75 mg/kg) of morphine. Withdrawal signs were elicited by naloxone (5mg/kg, i.p.) and number of jumpings and also presence of climbing, writing, wet dog shakes, teeth chattering, diarrhea, grooming and rearing during a 30 min period. Results: The ethanolic extract at all doses (100, 200 and 400 mg/kg, i.p., p <0.001) and fluoxetine (20mg/kg, i.p., p <0.01) significantly inhibited the number of jumps. Additionally, all doses of extract reduced the grooming and writing (p <0.05).Only 200 and 400 mg/kg of extract reduced the other checked signs including climbing, rearing and teeth chattering. All doses of extract couldn’t reduce wet dog shake and diarrhea significantly (p>0.05). Fluoxetine significantly inhibited the other signs except wet dog shakes and diarrhea. Conclusion: These findings indicated that Safflower extract has therapeutic potential in management of opiate withdrawal signs and this is comparable to the effect of fluoxetine. However, further studies need for clarify their exact mechanism of action.


Main Subjects

1. Stockton SD, Devi LA. Functional relevance of μ-δ opioid receptor heteromerization: a role in novel signaling and implications for the treatment of addiction disorders: from a symposium on new concepts in mu-opioid pharmacology. Drug Alcohol Depend. 2012; 121(3):167-72.
2. Kleber HD. Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues Clin Neurosci. 2007; 9(4): 455–70.
3. Abbasi Maleki F, Abbasi Maleki S, Mosavi S, Khayyatnouri MH. Effect of hydroalcoholic extract of Avena sativa L. on morphine withdrawal signs in male mice. J Sabzevar Univ Med Sci. 2014; 20(4): 408-15.
4. Abbasi Maleki N, Abbasi Maleki S, Bekhradi R. Suppressive effects of Rosa Damascena essential oil on naloxoneprecipitated morphine withdrawal signs in male mice. Iran J Pharm Res. 2013; 12(3): 357-61.
5. Hosseinzadeh H, Mahnaz Nourbakhsh. Effects of Rosmarinus officinalis L. aerial parts extract and fractions on morphine withdrawal syndrome in mice. Phytother Res. 2003 Sep; 17(8): 938-41.
6. Hosseinzadeh H, Jahanian Z. Effect of Crocus sativus L. (Saffron) stigma and its constituents, crocin and safranal, on morphine withdrawal syndrome in mice. Phytother Res. 2010; 24: 726-30.
7. Shahraki MR, Mirshekari H, Sabri A. Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in MorphineDependent Female Rats. Int J High Risk Behav Addict. 2014; 3(3): e11358.
8. Ahmadi Sheikh Sarmast H, Abbasi Maleki S. Naloxone-Precipitated morphine withdrawal in male mice is attenuated by acute administration of hydroalcoholic extract of Cymbopogon Citratus (Lemon Grass). India J Nat Sci. 2015. 5(28). 4743-4749.
9. Ramezani M, Hosseinzadeh H, Mojtahedi K. Effects of Ferula gummosa Boiss fractions on morphine dependence in mice. J Ethnopharmacol. 2001; 77(1): 71-5.
10. Punjanon T, Arpornsuwan T, Klinkusoom N. The pharmacological properties of safflower (Carthamus tinctorius L.). Bull of Health Sci and Tech. 2004; 7: 51-63.
11. Jun MS, Ha YM, Kim HS, Jang HJ, Kim YM, Lee YS, et al. Anti-inflammatory action of methanol extract of Carthamus tinctorius involves in heme oxygenase-1 induction. J Ethnopharmacol. 2011; 133(2): 524–30.
12. Rashmi Dehariya R, Dixit AK. A review on potential pharmacological uses of Carthamus tinctorius L. World J Pharm Sci. 2015; 3(8): 1741-6.
13. Loo WT, Cheung MN, Chow LW. The inhibitory effect of a herbal formula comprising ginseng and carthamus tinctorius on breast cancer. Life Sci. 2004; 76(2): 191-200.
14. Qazi N, Khan RA, Rizwani GH. Evaluation of antianxiety and antidepressant properties of Carthamus tinctorius L. (Safflower) petal extract. Pak J Pharm Sci. 2015; 28(3): 991-5.
15. Asgary S, Rahimi P, Mahzouni P, Madani H. Antidiabetic effect of hydroalcoholic extract of Carthamus tinctorius L. in alloxaninduced diabetic rats. J Res Med Sci. 2012;  17(4): 386-92.
16. Rabbani M, Jafarian A, Sobhanian M. Comparison between acute and long-term effects of verapamil on naloxane induced morphine withdrawal in mice. J Res Med Sci. 2004; 1: 26-33.
17. Qazi N, Khan RA, Rizwani GH. Evaluation of antianxiety and antidepressant properties of Carthamus tinctorius L. (Safflower) petal extract. Pak J Pharm Sci. 2015; 28(3): 991-5.
18. Wu CC, Chen JY, Tao PL, Chen YA, Yeh GC. Serotonin reuptake inhibitors attenuate morphine withdrawal syndrome in neonatal rats passively exposed to morphine. Eur J Pharmacol. 2005; 512(1): 37-42.
19. Singh VP, Jain NK, Kulkarni SK. Fluoxetine suppresses morphine tolerance and dependence: modulation of NO-cGMP/ DA/ serotoninergic pathways. Methods Find Exp Clin Pharmacol. 2003; 25(4): 273-80.
20. Garcia-Sevilla JA, Magnusson T, Carlsson A. Effects of enkephalins and two enzyme resistant analogues on monoamine synthesis and metabolism in rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1980; 310(3): 211-8.
21. Tao R, Auerbach SB. Increased extracellular serotonin in rat brain after systemic or intraraphe administration of morphine. J Neurochem. 1994. 63(2): 517-24.
22. Attila LMJ, Ahtee L. Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats. Naunyn Schmiedebergs Arch Pharmacol. 1984; 327(3): 201-7.
23. Bonci A, Williams JT. Increased probability of GABA release during withdrawal from morphine. J Neurosci. 1997; 17: 796–803.
24. Broseta I, Rodríguez-Arias M, Stinus L, Miñarro J. Ethological analysis of morphine withdrawal with different dependence programs in male mice. Prog Neuropsychopharmacol Biol Psychiatry. 2002; 26: 335-47.
25. Caille´ S, Espejo EF, Reneric JP, Cador M, Koob, GF, Stinus L. Total neurochemical lesion of noradrenergic neurons of the locus coeruleus does not alter either naloxone-precipitated or spontaneous opiate withdrawal nor does it influence ability of clonidine to reverse opiate withdrawal. J Pharmacol Exp Therapeutic.1999. 290:881–92.
26. Sakamura S, Terayama Y, Kawakatsu S, Ichihara A, Saito H. Conjugated Serotonins Related to Cathartic Activity in Safflower Seeds (Carthamus tinctorius L.), Agri Biol Chem.1978; 42:9: 1805-6.
27. Koyama N, Kuribayashi K, Seki T, Kobayashi K, Furuhata Y, Suzuki, K., et al. Serotonin derivatives, major safflower (Carthamus tinctorius L.) seed antioxidants, inhibit low-density lipoprotein (LDL) oxidation and atherosclerosis in apolipoprotein E-deficient mice. J Agric Food Chem. 2006; 12; 54(14):4970-6.
28. Feliciano AS, Medarde M, Del. Rey B, Del Corral JM, Barrero AF. Eudesmane glycosides from Carthamus lanatus. Phytochem. 1990; 29(10): 3207-11.
29. Lahloub M, Amor M, El-Khajaat S, Haraz F. A new serotonin derivative from seeds of Carthamuslanatus L. Mans J Pharm Sci. 1993; 9:234-43.
30. Sato S, Kusakari T, Suda T, Kasai T, Kumazawa T, Onodera J, et al. Efficient synthesis of analogs of safflower yellow B, carthamin, andits precursor: two yellow and one red dimericpigments in safflower petals. Tetrahedron. 2005; 61(40): 9630-6.
31. Zhao G, Gai Y, Chu WJ, Qin GW, Guo LH. A novel compound N1,N5-(Z)-N10- (E)-tri-p-coumaroyl spermidine isolated from Carthamus tinctorius L. and acting by serotonin transporter inhibition. Eur Neuropsychopharmacol. 2009; 19: 749-58.