Effects of crocin and safranal, saffron constituents, on the formalin-induced orofacial pain in rats

Document Type : Original Research Article

Authors

Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia Universiry, Urmia 57153-1177, I. R. Iran

Abstract

Objective: Crocin and safranal are the main components of saffron, and have many biological functions such as anti-inflammatory and antioxidant activities. In the present study, we investigated the effects of crocin, safranal, morphine, diclofenac and naloxone in combined and separately on formalin-induced orofacial pain in rats.
Materials and Methods: Subcutaneous injection of a diluted formalin solution (50 µl, 1.5%) into the upper lip region produced a biphasic pattern of pain response (a neurogenic phase: 0-3 min and an inflammatory phase: 15-33 min). The time each animal spent face rubbing with ipsilateral forepaw was recorded and considered as an index of nociception
Results: Intraperitoneal injections of crocin (12.5 and 25 mg/kg), safranal (0.25 and 0.5 mg/kg), diclofenac (5 and 10 mg/kg) and morphine (1 and 2 mg/kg) suppressed the second phase of pain. The second phase of pain was also reduced when low (ineffective) doses of crocin (6.25 mg/kg) and safranal (0.125 mg/kg) were co-administered with low doses of diclofenac (2.5 mg/kg) and morphine (0.5 mg/kg). The more antinociceptive effects were observed when the medium doses of the above-mentioned chemicals used together. Naloxone prevented morphine-induced antinociception, but did not inhibit the suppressive effects of crocin and safranal. Safranal at a high dose (0.5 mg/kg) suppressed locomotor activity.
Conclusion: The present results showed antinociceptive effects for crocin and safranal in inflammatory pain. Opioid receptors may not be involved in the antinociceptive effect of crocin and safranal. Crocin and safranal increased diclofenac-induced antinociception.

Keywords

Main Subjects


Abbott FV, Bonder M. 1997. Options for management of acute pain in the rat. Vet Rec, 140: 553-557.
Amin B, Hosseinzadeh H. 2012. Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L, and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats. Fitoterapia, 83: 888-895.
Assimopolou AN, Sinakos Z, Papageorgiou VP. 2005. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res, 19: 997-1000.
Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Shegal N, Glaser SE, Vallejo R. 2008. Opioid complications and side effects. Pain Physician, 11: S105-S120.
Bongenhielm U, Boissonade FM, Westermark A, Robinson,PP, Fried K. 1999. Sympathetic nerve sprouting fails to occur in the trigeminal ganglion after peripheral nerve injury in the rat. Pain, 82: 283-288.
Boskabady MH, Tabatabaee A, Byrami G. 2012. The effect of the extract of Crocus sativus and its constituent safranal, on lung inflammation of ovalbumin sensitized guinea-pigs. Phytomedicine, 19: 904-911.
Burgos E, Pascual D, Martin MI, Goicoechea C. 2010. Antinociceptive effect of cannabinoid agonist, WIN 55, 212-2, in the orofacial and temporomandibular formalin test. Eur J Pain, 14: 40-48.
Chichorro JG, Lorenzetti BB, Zampronio AR. 2004. Involvement of bradykinin, cytokines, sympathetic amines and prodtaglandins in formalin-induced orofacial nociception in rats. Br J Pharmacol, 141: 1175-1184.
Clavelou P, Dallel R, Orliaquest T, Woda A, Raboisson P. 1995. The orofacial formalin test in rats: effects of different formalin concentrations. Pain, 62: 295-301.
Clavelou P, Pajot J, Dallel R, Raboisson P. 1989. Application of the formalin test to the study of orofacial pain in the rat. Neurosci Lett, 103: 349-353.
Cristiano MP, CardosoDC, de Siva Panula MM, Costa-Campos L. 2008. Antinociceptive effect of a ruthenium complex in mice. Auton Autacoid Pharmacol, 28: 103-108.
Curatolo M, Sveticic G. 2002. Drug combination in pain treatment: a review of the published evidence and a method for finding the optimal combination. Best Prac Res Clin Anaesthesiol, 16: 507-519.
Duale C, Sierralta F, Dallel R. 2007. Analgesia induced by morphine microinjected into the nucleus raphe magnus: effect on tonic pain. Curr Drug Deliv, 4: 181-184.
Eisenberg E, Vos BP, Strassman AM. 1996. The peripheral antinociceptive effect of morphine in a rat model of facial pain. Neuroscience, 72: 519-525.
Erfanparast A, Escort M, Tamaddonfard E, Maroufi S, Kazemi- Shojaei S,  Dabbaghi M, Taati M. 2014. Systemic and local peripheral injections of vitamin B12 suppressed orofacial nociception induced by formalin in rats. Drug Res (Stuttg), 64: 85-90.
Farshid AA, Tamaddonfard E, Yahyaee F. 2010. Effects of histidine and N-acetylcysteine on diclofenac-induced anti-inflammatory response in acute inflammation in rats. Indian J Exp Biol, 48: 1136-1142.
Gadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, Haghighi S, Sameni HR, Pahlavan S. 2011. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficts induced by chronic stress in rats. Eur J Pharmacol, 667: 222-229.
Ganzberg S. 2010. Pain management part II: Pharmacological management of chronic orofacial pain. Anesth Prog, 57: 114-118.
Grabow TS, Dougherty PM. 2001. Cervicomedullary intrathecal injection of morphine produces antinociception in the orofacial formalin test in the rat. Anesthesiology, 95: 1427-1434.
Guy N, Chalus M, Dallel R, Voisin DL. 2005. Both oral and caudal parts of the spinal trigeminal nucleus project to the somatosensory thalamus in the rat. Eur J Neurosci, 21: 741-754.
Hemshekhar M, Sebastian Santhosh M, Sunitha K, Thushara, RM, Kemparaju K, Rangappa KS, Girish K. 2012. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating, inflammatory mediators and antioxidant status. Biochimie, 94: 2723-2733.
Hosseinzadeh H, NoraeiNB. 2009. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res, 23: 768-774.
Hosseinzadeh H, Shariaty V (2007). Antinociceptive effects of safranal, a constituent of Crocus sativus (saffron), in mice. Pharmacologyonline, 2: 498-503
Luccarini P, Cadet R, Saade M, Woda A. 1995. Antinociceptive effect of morphine microinjections into the spinal trigeminal subnucleus oralis. Neuroreport 6: 365-368.
Markowska A, LukaszewskaI. 1981. Open-field behavior in rats with frontomedial cortical, neostratal or hippocampal lesions. Acta Neurobiol Exp, 41: 197-210.
Maroon JC, Bost JW, Marron A. 2010. Natural anti-inflammatory agents for pain relief. Surg Neurol Int, 1: 80.
Melnyk JP, Wang S, Marcone MF. 2010. Chemical and biological properties of the worldʼs most expensive spice: Saffron. Food Res Int, 43: 1981-1989
Miranda HF, Noriegam V, Sierralta F, Prieto JC. 2011. Interaction between dexibuprofen and dexketoprofen in the orofacial formalin test in mice. Pharmacol Biochem Behav, 97: 423-427.
Nam KN, Park YM, Jung HJ, Lee JY, Min BD, Park SU, Jung WS, Cho KH, Kang I, Hong JW, Lee EH. 2010. Anti-inflammatory effects of crocin and crocetin in rats brain microglial cells. Eur J Pharmacol, 648: 110-116.
Padi SS, Naidu PS, Kulkarni SK. 2006. Involvement of peripheral prostaglandins in formalin-induced nociceptive behaviors in the orofacial area of rats. Inflammopharmacology, 14: 57-61.
PorroCA, Cavazzuti M. 1993. Spatial and temporal aspects of spinal cord and brainstem activation in the formalin pain model. Prog Neurobiol, 41: 565-607.
Rios JL, Recio MC, Ginger RM, Manz S. 1996. An update review of saffron and its active constituents. Phytother Res, 10: 189-193.
Raboisson P, Dallel R. 2004. The orofacial formalin test. Neurosci Biobehav Rev, 28: 219-226.
Sarlani E, Balciunas BA, Grace EG. 2005. Orofacial pain—Part I: Assessment and management of musculoskeletal and neuropathologic causes. AACN Clin Issues, 16: 333-346.
Schmidt M, Betti G, Hensel A. 2007. Saffron in phytotherapy: pharmacology and clinical uses.  Wien Med Wochenschr, 157: 315-319.
Sessle BJ. 2011. Peripheral and central mechanisms of orofacial inflammatory pain. Int Rev Neurobiol, 97: 179-206.
Suleyman H, Demican B, Karagoz Y. 2007. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep, 59: 247-258.
Tal M, Devor M. 1992. Ectopic discharge in injured nerves: comparison of trigeminal and somatic afferent. Brain research, 579: 148-151.
Tamaddonfard E, Farshid AA, Ahmadian E, Hamidhoseyni A. 2013a. Crocin enhanced functional recovery after sciatic nerve crush injury in rats. Iran J Basic Med Sci, 16: 83-90.
Tamaddonfard E, Farshid AA, Asri-Rezaee S, Javadi S, Khosravi V, Rahman B, Mirfakhraee Z. 2013b. Crocin improved learning and memory impairments in streptozotocin-induced diabetic rats. Iran J Basic Med Sci, 16: 91-100.
Tamaddonfard E, Farshid AA, Eghdami K, Samadi F, Erfanparast A. 2013c. Comparison of the effects of crocin, safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats. Pharmacol Rep, 65: 1272-1280
Tamaddonfard E, Farshid AA, Maroufi S, Kazemi-Shojaei  S, Erfanparst A, Asri-Rezaei S, Taati M, Dabbaghi M, Escort M. 2014. Effects of saffranal, a constituent of saffron, and vitamin E on nerve functions and histopathology following crush injury of sciatic nerve in rats. Phytomedicine, 21: 717-723.
Tamaddonfard E, Samadi F, Egdami K. 2013e. The effects of vitamin B12 and diclofenac and their combination on cold and mechanical allodynia in a neuropathic pain model in rats. Vet Res Forum, 4: 19-24.
Tamaddonfard E, Hamzeh Gooshchi N, Seiednejhad-Yamchi S. 2012. Central effect of crocin on penicillin-induced epileptiform activity in rats. Pharmacol Rep, 64: 94-101.
Tamaddonfard E, Erfanparast A, Farshid AA, Khalilzadeh E. 2011. Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats. Pharmacol Rep, 63: 423-432.
Tamaddonfard E, Hamzeh-Gooshchi N. 2010a. Effect of crocin on the morphine-induced antinociception in the formalin test in rats. Phytother Res, 24: 410-413.
Tamaddonfard E, Hamzeh-Gooshchi N. 2010b. Effects of intraperitoneal and intracerebroventricular injection of crocin on acute corneal pain in rats. Phytother Res, 24: 1463-1467.
Tjolsen A, Berge OG, Hunskaar S, Rosland GH, Hole K. 1992. The formalin test: an evaluation of the method. Pain, 51: 5-17.
Torpe LB, Goldie M, Dolan S. 2011. Central and local administration of Gingko biloba extract EGb 761 ® inhibits thermal hyperalgesia and inflammation in the rat carrageenan model. Anesth Analg, 112: 1226-1231.
Vane JR, Botting RM. 1996. Mechanisms of action of anti-inflammatory drugs. Scand J Rheumatol, 102: 9–21.
Wolfe MM, Lichtenstein DR, Singh G. 1999. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med, 370: 1888-1899.
Xu GL, Li G, Ma HP, Zhong H, Liu F, Ao GZ. 2009. Preventive effect of crocin in inflamed animals and in LPS-challenged RAW 264.7 cells. J Agric Food Chem, 57: 8325-8330.