Effect of the methanolic extracts of different parts of Ferula assa-foetida on naloxone-induced withdrawal behavior in morphine-dependent mice

Document Type: Original Research Article


1 Faculty of Land and Food Systems, University of British Columbia, Vancouver, BC, Canada Department of Pharmacognosy, Faculty of Pharmacy and Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.

2 Department of Pharmacognosy, Faculty of Pharmacy and Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Toxicology and Pharmacology and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.


Objective: Ferula assa-foetida, a native species in Iran, is used for treatment of several diseases particularly for neurological disorders in Iranian Traditional Medicine. The aim of this study is to investigate the effect of methanolic roots, fruits, and aerial parts extracts of Ferula assa-foetida on withdrawal syndrome in morphine-dependent mice.
Materials and Methods: Aerial parts, roots, and fruits of the plant were separately extracted with 80% MeOH. For induction of dependence, morphine (50, 50 and 75 mg/kg) was injected subcutaneously three times daily (10 am, 1 pm and 4 pm) for three days and a last dose of morphine (50 mg/kg) was administrated on the fourth day. Withdrawal syndrome was induced by injection of naloxone (5 mg/kg, intraperitoneal) 2 hr after the final dose of morphine. Different doses of the extracts were administered i.p. 60 minutes before naloxone injection and withdrawal sign was recorded 2 minutes after naloxone injection for a period of 60 minutes.  
Results: Pre-treatment of animals with different doses (2.5, 5, 10, 20 mg/kg) of methanolic extract of the aerial parts of F. assa-foetida caused a significant decrease in naloxone-induced behavior. Intraperitoneal administration of different doses (10, 15, 20, 25 mg/kg) of methanolic extract of the fruit significantly reduced the naloxone-induced withdrawal behavior (p<0.001).
Conclusion: It might be concluded that the extracts of Ferula assa-foetida affect morphine withdrawal syndrome possibly via interference with the neurotransmitters in nervous system.


Main Subjects

Abd El‐Razek MH, Wu YC, Chang FR. 2007. Sesquiterpene coumarins from Ferulafoetida. J Chin Chem Soc, 54:235-238.

Ambrosio E, Iglesias V, García-Lecumberri C, Orensanz L, Alguacil LF. 1997. Effect of Yohimbine on the Development of Morphine Dependence in the Rat: Lack of Involvement of Cortical β-adrenoceptor Modifications. Pharmacol Biochem Behav, 56:487-491.

Aoshima H, Hamamoto K. 1999. Potentiation of GABAA receptors expressed in Xenopus oocytes by perfume and phytoncid. Biosci Biotechnol Biochem, 63: 743-748.

Bagheri S, Dashti-R M, Morshedi A. 2014. Antinociceptive effect of Ferula assa-foetida oleo-gum-resin in mice. Res Pharm Sci, 9:207.

Bailey A, Davis L, Lesscher H, Kelly MD, Ledent C, Hourani SM, Kitchen I. 2004. Enhanced morphine withdrawal and µ‐opioid receptor G‐protein coupling in A2A adenosine receptor knockout mice. J Neurochem, 88:827-834.

Bamoniri A, Mazoochi A. 2009. Determination of bioactive and fragrant molecules from leaves and fruits of Ferula assa-foetida L. growing in central Iran by nanoscal injection. Digest J Nanomater Biostruct, 4:323-328.

Bandyopadhyay D, Basak B, Chatterjee A, Lai TK, Banerji A, Banerji J, Neuman A, Prangé T. 2006. Saradaferin, a new sesquiterpenoid coumarin from Ferula assafoetida. Nat Prod Res, 20:961-965.

Bederson JB, Fields HL, Barbaro NM. 1990. Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla. Somatosens Mot Res, 7:185-203.

Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AMG. 2007. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci, 8:766-775.

Cao J-L, Liu H-L, Wang J-K, Zeng Y-M. 2006. Cross talk between nitric oxide and ERK1/2 signaling pathway in the spinal cord mediates naloxone-precipitated withdrawal in morphine-dependent rats. Neuropharmacology, 51:315-326.

Chartoff EH, Barhight MF, Mague SD, Sawyer AM, Carlezon WA. 2009. Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats. Psychopharmacology, 204:227-239.

Cheng C-y, Su S-y, Tang N-y, Ho T-y, Lo W-y, Hsieh C-l. 2010. Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABAB1 receptor expression in transient focal cerebral ischemia in rats. Acta Pharmacol Sin, 31:889-899.

Desarmenien M, Feltz P, Occhipinti G, Santangelo F, Schlichter R. 1984. Coexistence of GABAA and GABAB receptors on Aδ and C primary afferents. Br J Pharmacol, 81:327-333.

Eigner D, Scholz D. 1999. Ferula asa-foetida and Curcuma longa in traditional medical treatment and diet in Nepal. J Ethnopharmacol, 67:1-6.

Fatehi M, Farifteh F, Fatehi-Hassanabad Z. 2004. Antispasmodic and hypotensive effects of Ferula asafoetida gum extract. J Ethnopharmacol, 91:321-324.

Gabra BH, Bailey CP, Kelly E, Smith FL, Henderson G, Dewey WL. 2008. Pre-treatment with a PKC or PKA inhibitor prevents the development of morphine tolerance but not physical dependence in mice. Brain Res, 1217:70-77.

García DA, Bujons J, Vale C, Suñol C. 2006. Allosteric positive interaction of thymol with the GABA A receptor in primary cultures of mouse cortical neurons. Neuropharmacology, 50:25-35.

Gholamnezhad Z, Byrami G, Boskabady MH, Iranshahi M. 2012. Possiblemechanism (s) of the relaxant effect of asafoetida (Ferula assa-foetida) oleo-gum-resin extract on guinea-pig tracheal smooth muscle. Avicenna J Phytomed, 2.

Granger RE, Campbell EL, Johnston GA. 2005. (+)-And (−)-borneol: efficacious positive modulators of GABA action at human recombinant α 1 β 2 γ 2L GABA A receptors. Biochem Pharmacol, 69:1101-1111.

Iranshahy M, Iranshahi M. 2011. Traditional uses, phytochemistry and pharmacology of asafoetida (Ferula assa-foetida oleo-gum-resin)—A review. J Ethnopharmacol, 134:1-10.

Jadidi M, Vafaie A, Miladi Gorji H, Babaie Saeidabadi A. 2011. The effect of Ferula persica L extracts on symptoms of morphine withdrawal and sleeping time in mice. J Res Med Sci, 34:225-230.

Khajeh M, Yamini Y, Bahramifar N, Sefidkon F, Pirmoradei MR. 2005. Comparison of essential oils compositions of Ferula assa-foetida obtained by supercritical carbon dioxide extraction and hydrodistillation methods. Food Chem, 91:639-644.

Koh P-O. 2012. Ferulic acid modulates nitric oxide synthase expression in focal cerebral ischemia. Lab Anim Res, 28:273-278.

Kuriyama K, Yoneda Y. 1978. Morphine induced alterations of γ-aminobutyric acid and taurine contents and l-glutamate decarboxylase activity in rat spinal cord and thalamus: Possible correlates with analgesic action of morphine. Brain Res, 148:163-179.

Lee C-L, Chiang L-C, Cheng L-H, Liaw C-C, Abd El-Razek MH, Chang F-R, Wu Y-C. 2009. Influenza A (H1N1) antiviral and cytotoxic agents from Ferula assa-foetida. J Nat Prod, 72:1568-1572.

Liapi C, Anifantis G, Chinou I, Kourounakis AP, Theodosopoulos S, Galanopoulou P. 2007. Antinociceptive properties of 1, 8-cineole and β-pinene, from the essential oil of Eucalyptus camaldulensis leaves, in rodents. Planta Med, 73:1247-1254.

Melo FHC, Moura BA, de Sousa DP, de Vasconcelos SMM, Macedo DS, Fonteles MMdF, Viana GSdB, de Sousa FCF. 2011. Antidepressant‐like effect of carvacrol (5‐Isopropyl‐2‐methylphenol) in mice: involvement of dopaminergic system. Fundam Clin Pharmacol, 25:362-367.

Melo FHC, Venâncio ET, De Sousa DP, De França Fonteles MM, De Vasconcelos SMM, Viana GSB, De Sousa FCF. 2010. Anxiolytic‐like effect of Carvacrol (5‐isopropyl‐2‐methylphenol) in mice: involvement with GABAergic transmission. Fundam Clin Pharmacol, 24:437-443.

Mohajel Naebi AR, Asadi M. 2009. Effect of buspirone on morphine withdrawal syndrome in mice. Pharm Sci, 14:229-235.

Quintans-Júnior LJ, Guimarães AG, Araújo BE, Oliveira GF, Santana MT, Moreira FV, Santos MR, Cavalcanti SC, Júnior WL, Botelho MA. 2010. Carvacrol,(-)-borneol and citral reduce convulsant activity in rodents. AfrJ Biotechnol, 9:6566-6572.

Ramezani M, Hosseinzadeh H, Mojtahedi K. 2001. Effects of Ferula gummosa Boiss. fractions on morphine dependence in mice. J Ethnopharmacol, 77:71-75.

Riahi E, Mirzaii-Dizgah I, Karimian SM, Roodsari HRS, Dehpour AR. 2009. Attenuation of morphine withdrawal signs by a GABA B receptor agonist in the locus coeruleus of rats. Behav Brain Res, 196:11-14.

Samadi N, Shahani S, Akbarzadeh H, Mohammadi-Motamed S, Safaripour E, Farjadmand F, Eftekhari M, Monsef-Esfahani H, Khanavi M. 2016. Essential oil analysis and antibacterial activity of Ferula assa-foetida L. aerial parts from Neishabour mountains. Res J Pharmacogn, 3:35-42.

Schulz S, Höllt V. 1998. Opioid withdrawal activates MAP kinase in locus coeruleus neurons in morphine‐dependent rats in vivo. Eur J Neurosci, 10:1196-1201.

Song J-J, Gu Cho J, Hwang S-J, Gun Cho C, Park S-W, Chae S-W. 2008. Inhibitory effect of caffeic acid phenethyl ester (CAPE) on LPS-induced inflammation of human middle ear epithelial cells. Acta Oto-Laryngol, 128:1303-1307.

Sung CS, Wen ZH, Chang WK, Chan KH, Ho ST, Tsai SK, Chang YC, Wong CS. 2005. Inhibition of p38 mitogen‐activated protein kinase attenuates interleukin‐1β‐induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. J Neurochem, 94:742-752.

Toda N, Kishioka S, Hatano Y, Toda H. 2009. Modulation of opioid actions by nitric oxide signaling. The Journal of the American Society of Anesthesiologists, 110:166-181.

Waliwitiya R, Belton P, Nicholson RA, Lowenberger CA. 2010. Effects of the essential oil constituent thymol and other neuroactive chemicals on flight motor activity and wing beat frequency in the blowfly Phaenicia sericata. Pest Manag Sci, 66:277-289.

Zarrindast M-R, Mousa-Ahmadi E. 1999. Effects of GABAergic system on naloxone-induced jumping in morphine-dependent mice. Eur J Pharmacol, 381:129-133.

Zotti M, Colaianna M, Morgese MG, Tucci P, Schiavone S, Avato P, Trabace L. 2013. Carvacrol: from ancient flavoring to neuromodulatory agent. Molecules, 18:6161-6172.