α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide

Document Type : Original Article


1 Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran


Objective(s):Dependence and tolerance to opioid analgesics are major problems limiting their clinical application. a-Terpineol is a monoterpenoid alcohol with neuroprotective effects which is found in several medicinal plants such as Myrtus communis, Laurus nobilis, and Stachys byzantina. It has been shown that some of these medicinal plants such as S. byzantina attenuate dependence and tolerance to morphine. Since a-terpineol is one of the bioactive phytochemical constituent of these medicinal plants, the present study was conducted to investigate the effects of a-terpineol on morphine-induced dependence and tolerance in mice.
Materials and Methods: The mice were rendered dependent or tolerant to morphine by a 3-day administration schedule. The hot-plate test and naloxone-induced withdrawal syndrome were used to evaluate tolerance and dependence on morphine, respectively. To investigate a possible role for nitric oxide (NO) in the protective effect of a-terpineol, the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) and NO precursor, L-arginine, were used.
Results: Administration of a-terpineol (5, 10, and 20 mg/kg, IP) significantly decreased the number of jumps in morphine dependent animals. Moreover, a-terpineol (20 and 40 mg/kg, IP) attenuated tolerance to the analgesic effect of morphine. The inhibitory effects of a-terpineol on morphine-induced dependence and tolerance were enhanced by pretreatment with L-NAME (10 mg/kg, IP). However, L-arginine (300 mg/kg, IP) antagonized the protective effects of a-terpineol on dependence and tolerance to morphine.
Conclusion: These findings indicate that a-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production.


1. Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, et al. Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2013.
2. Tabatabai SM, Dashti S, Doosti F, Hosseinzadeh H. Phytotherapy of opioid dependence and withdrawal syndrome: a review. Phytother Res 2014; 28:811-830.
3. Shokraviyan M, Miladi-Gorji H, Vaezi GH. Voluntary and forced exercises prevent the development of tolerance to analgesic effects of morphine in rats. Iran J Basic Med Sci 2014;17:271-277.
4. Adnan LH, Bakar NH, Mohamad N. Opioid dependence and substitution therapy: thymoquinone as potential novel supplement therapy for better outcome for methadone maintenance therapy substitution therapy. Iran J Basic Med Sci 2014;17: 926-928.
5. Bakkali F, Averbeck S, Averbeck D, Idaomar M. Biological effects of essential oils- a review. Food Chem Toxicol 2008; 46:446-475.
6. Aprotosoaie AC, Hăncianu M, Costache II, Miron A. Linalool: a review on a key odorant molecule with valuable biological properties. Flavour Fragr J 2014; 29:193-219.
7. Guimarães AG, Quintans JSS, Quintans-Júnior LJ. Monoterpenes with analgesic activity- A systematic review. Phytother Res 2013; 27:1-15.
8. Dobetsberger C, Buchbauer G. Actions of essential oils on the central nervous system: An updated review. Flavour Fragr J 2011;26:300-316.
9. El-Ghorab A, El-Massry KF, Shibamoto T. Chemical composition of the volatile extract and antioxidant activities of the volatile and nonvolatile extracts of Egyptian Corn Silk (Zea mays L.). J Agric Food Chem 2007;55:9124-9127.
10. Bicas JL, Neri-Numa IA, Ruiz ALTG, De Carvalho JE, Pastore GM. Evaluation of the antioxidant and antiproliferative potential of bioflavors. Food Chem Toxicol 2011; 49:1610-1615.
11. de Sousa DP, Quintans L, de Almeida RN. Evolution of the anticonvulsant activity of α-terpineol. Pharm Biol 2007; 45:69-70.
12. de Oliveira MG, Marques RB, de Santana MF, Santos AB, Brito FA, Barreto EO, et al. α-Terpineol reduces mechanical hypernociception and inflammatory response. Basic Clin Pharmacol Toxicol 2012; 111:120-125.
13. Quintans-Júnior LJ, Oliveira MG, Santana MF, Santana MT, Guimarães AG, Siqueira JS, et al. α-Terpineol reduces nociceptive behavior in mice. Pharm Biol 2011; 49:583-586.
14. Rahimi-Nasrabadi M, Nazarian S, Farahani H, Fallah Koohbijari GR, Ahmadi F, Batooli H. Chemical composition, antioxidant, and antibacterial activities of the essential oil and methanol extracts of Eucalyptus largiflorens F. Muell. Int J Food Prop 2013; 16:369-381.
15. Gilles M, Zhao J, An M, Agboola S. Chemical composition and antimicrobial properties of essential oils of three Australian Eucalyptus species. Food Chem 2010; 119:731-737.
16. Ben Hsouna A, Hamdi N, Miladi R, Abdelkafi S. Myrtus communis essential oil: chemical composition and antimicrobial activities against food spoilage pathogens. Chem Biodivers 2014; 11:571-580.
17. Salehi Surmaghi MH, Amin G, Shakibafar A, Azadi B. Unexpected volatile compounds of myrtus communis L. fruit rind growing in Iran. Int J Biol Pharm Res 2014; 5:428-431.
18. Khan M, Al-Mansour MA, Mousa AA, Alkhathlan HZ. Compositional characteristics of the essential oil of Myrtus communis grown in the central part of Saudi Arabia. J Essent Oil Res 2014; 26:13-18.
19. Abu-Dahab R, Kasabri V, Afifi FU. Evaluation of the volatile oil composition and antiproliferative activity of Laurus nobilis L. (Lauraceae) on breast cancer cell line models. Rec Nat Prod 2014; 8:136-147.
20. Mostafavi H, Mousavi SH, Zalaghi A, Delsouzi R. Chemical composition of essential oil of Stachys byzantina from North-West Iran. J Essent Oil Bear Plant 2013; 16:334-337.
21. Hosseinzadeh H, Dowlati S, Etemad L. Effects of Stachys byzantina C. Koch aerial parts aqueous extract on morphine dependence and tolerance in mice. Pharmacologyonline 2008; 2:614-617.
22. Özek M, Üresin Y, Güngör M. Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia, tolerance and dependence in mice. Life Sci 2003;72:1943-1951.
23. Abdel-Zaher AO, Mostafa MG, Farghaly HSM, Hamdy MM, Abdel-Hady RH. Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid. Behav Brain Res 2013; 247:17-26.
24. Abdel-Zaher AO, Abdel-Rahman MS, ELwasei FM. Blockade of nitric oxide over-production and oxidative stress by Nigella sativa oil attenuates morphine-induced tolerance and dependence in mice. Neurochem Res 2010; 35:1557-1565.
25. Hosseinzadeh H, Parvardeh S, Masoudi A, Moghimi M, Mahboobifard F. Attenuation of morphine tolerance and dependence by thymoquinone in mice. Avicenna J Phytomed 2016; 6: 55-66.
26. Parvardeh S, Nassiri Asl M, Niapoor M, Hosseinzadeh H. Antinociceptive, anti-inflammatory and acute toxicity effects of Pistacia Vera L. gum extract in mice and rat. J Med Plant 2002; 4:58-67.
27. Parvardeh S, Hosseinzadeh H. Hypnotic and muscle relaxant activity of thymoquinone, the major active constituent of Nigella sativa seeds, and its effects on locomotor activity and motor coordination in mice. J Med Plant 2003; 4:17-26.
28. Imenshahidi M, Hosseinzadeh H, Es'haghian A. Effects of ethosuximide on morphine tolerance and dependence in mice. Pharmacologyonline 2007; 2:287-299.
29. Kandel ER, Schwartz JH. Principles of Neural Science. 5th ed. McGraw-Hill; 2013.
30. Vaupel DB, Kimes AS, London ED. Further in vivo studies on attenuating morphine withdrawal: isoform-selective nitric oxide synthase inhibitors differ in efficacy. Eur J Pharmacol 1997; 324:11-20.
31. Abdel-Zaher AO, Hamdy MM, Aly SA, Abdel-Hady RH, Abdel-Rahman S. Attenuation of morphine tolerance and dependence by aminoguanidine in mice. Eur J Pharmacol 2006; 540:60-66.
32. Abdel-Zaher AO, Mostafa MG, Farghly HM, Hamdy MM, Omran GA, Al-Shaibani NK. Inhibition of brain oxidative stress and inducible nitric oxide synthase expression by thymoquinone attenuates the development of morphine tolerance and dependence in mice. Eur J Pharmacol 2013; 702:62-70.
33. Majeed NH, Przewłocka B, Machelska H, Przewłocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology 1994; 33:189-192.
34. Cappendijk SL, de Vries R, Dzoljic MR. Inhibitory effect of nitric oxide (NO) synthase inhibitors on naloxone-precipitated withdrawal syndrome in morphine-dependent mice. Neurosci Lett 1993; 162:97-100.
35. Özek M, Üresin Y, Güngör M. Comparison of the effects of specific and nonspecific inhibition of nitric oxide synthase on morphine analgesia, tolerance and dependence in mice. Life Sci 2003; 72:1943-1951.
36. Homayoun H, Khavandgar S, Namiranian K, Dehpour AR. The effect of cyclosporin A on morphine tolerance and dependence: involvement of L-arginine/nitric oxide pathway. Eur J Pharmacol 2002; 452:67-75.
37. Vuong QV, Hirun S, Chuen TL, Goldsmith CD, Munro B, Bowyer MC, et al. Physicochemical, antioxidant and anti-cancer activity of a Eucalyptus robusta (Sm.) leaf aqueous extract. Indust Crop Prod 2015;64:167-174.
38. Al-Sayed E, El-Naga RN. Protective role of ellagitannins from Eucalyptus citriodora against ethanol-induced gastric ulcer in rats: Impact on oxidative stress, inflammation and calcitonin-gene related peptide. Phytomedicine 2015; 22:5-15.
39. Goudjil MB, Ladjel S, Bencheikh SE, Zighmi S, Hamada D. Study of the chemical composition, antibacterial and antioxidant activities of the essential oil extracted from the leaves of Algerian Laurus nobilis Lauraceae. J Chem Pharm Res 2015; 7:379-385.
40. Cherrat, L, Espina, L, Bakkali, M, García‐Gonzalo, D, Pagán, R, Laglaoui, A. Chemical composition and antioxidant properties of Laurus nobilis L. and Myrtus communis L. essential oils from Morocco and evaluation of their antimicrobial activity acting alone or in combined processes for food preservation. J Sci Food Agric 2014; 94:1197-1204.
41. El SN, Karagozlu N, Karakaya S, Sahın S. Antioxidant and antimicrobial activities of essential oils extracted from Laurus nobilis L. leaves by using solvent-free microwave and hydrodistillation. Food Nutr Sci 2014; 5:97-106.
42. Asnaashari S, Delazar A, Alipour SS, Nahar L, Williams AS, Pasdaran A, et al. Chemical composition, free-radical-scavenging and insecticidal activities of the aerial parts of Stachys byzantina. Arch Biol Sci 2010; 62:653-662.