期刊论文详细信息
BMC Complementary and Alternative Medicine
Antinociceptive activity of methanolic extract of Muntingia calabura leaves: further elucidation of the possible mechanisms
Mohd Zaki Salleh1  Teh Lay Kek1  Arifah Abdul Kader2  Manraj Singh Cheema3  Mohd Hijaz Mohd Sani3  Zainul Amiruddin Zakaria1 
[1] Integrative Pharmacogenomics Institute (iPROMISE), Level 7, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Puncak Alam, Selangor, Malaysia;Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia;Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
关键词: Mechanisms of action;    Antinociceptive activity;    Methanol extract;    Elaecocarpaceae;    Muntingia calabura;   
Others  :  1220258
DOI  :  10.1186/1472-6882-14-63
 received in 2013-10-17, accepted in 2014-02-11,  发布年份 2014
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【 摘 要 】

Background

Muntingia calabura (Elaecoparceae) is a medicinal plant traditionally used, particularly, by the Peruvian people to alleviate headache and cold, pain associated with gastric ulcers or to reduce the prostate gland swelling. Following the recent establishment of antinociceptive activity of M. calabura leaf, the present study was performed to further elucidate on the possible mechanisms of antinociception involved.

Methods

The methanol extract of M. calabura (MEMC) was prepared in the doses of 100, 250 and 500 mg/kg. The role of bradykinin, protein kinase C, pottasium channels, and various opioid and non-opioid receptors in modulating the extract’s antinociceptive activity was determined using several antinociceptive assays. Results are presented as Mean ± standard error of mean (SEM). The one-way ANOVA test with Dunnett's multiple comparison was used to analyze and compare the data, with P < 0.05 as the limit of significance.

Results

The MEMC, at all doses, demonstrated a significant (p < 0.05) dose-dependent antinociceptive activity in both the bradykinin- and phorbol 12-myristate 13-acetate (PMA)-induced nociception. Pretreatment of the 500 mg/kg MEMC with 10 mg/kg glibenclamide (an ATP-sensitive K+ channel inhibitor), the antagonist of μ-, δ- and κ-opioid receptors (namely 10 mg/kg β-funaltrexamine, 1 mg/kg naltrindole and 1 mg/kg nor-binaltorphimine), and the non-opioid receptor antagonists (namely 3 mg/kg caffeine (a non-selective adenosinergic receptor antagonist), 0.15 mg/kg yohimbine (an α2-noradrenergic antagonist), and 1 mg/kg pindolol (a β-adrenoceptor antagonist)) significantly (p < 0.05) reversed the MEMC antinociception. However, 10 mg/kg atropine (a non-selective cholinergic receptor antagonist), 0.15 mg/kg prazosin (an α1-noradrenergic antagonist) and 20 mg/kg haloperidol (a non-selective dopaminergic antagonist) did not affect the extract's antinociception. The phytochemicals screening revealed the presence of saponins, flavonoids, tannins and triterpenes while the HPLC analysis showed the presence of flavonoid-based compounds.

Conclusions

The antinociceptive activity of MEMC involved activation of the non-selective opioid (particularly the μ-, δ- and κ-opioid) and non-opioid (particularly adenosinergic, α2-noradrenergic, and β-adrenergic) receptors, modulation of the ATP-sensitive K+ channel, and inhibition of bradikinin and protein kinase C actions. The discrepancies in MEMC antinociception could be due to the presence of various phytochemicals.

【 授权许可】

   
2014 Zakaria et al.; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Raj PP: Pain Medicine: A Comprehensive Review. 2nd edition. Texas: Mosby Inc; 2003.
  • [2]Strong J, Unruh AM, Wright A, Baxter GD, Wall PD: Pain: a textbook for therapists. London: Churchill Livingstone; 2002.
  • [3]Hawthorn J, Redmond K: Pain: causes and management. Oxford: Blackwell Science Ltd; 1998.
  • [4]Paris PM, Stewart RD: Pain management in emergency medicine. Connecticut: Appleton and Lange; 1988.
  • [5]Katzung BG: Basic and Clinical Pharmacology. 9th edition. 2004. International Edition
  • [6]Holt GA, Chandra A: Herbs in the modern healthcare environment-an overview of uses, legalities and the role of the healthcare professional. Clin Res Regul Aff (USA) 2002, 19:83-107.
  • [7]Rates SMK: Plants as source of drugs. Toxicon 2001, 29:603.
  • [8]Kaneda N, Pezzuto JM, Soejarto DD, Kinghorn AD, Farnsworth NR, Santisuk T, Tuchinda P, Udchachon J, Reutrakul V: Plant anticancer agents, XLVIII. New cytotoxic flavonoids from Muntingia calabura roots. J Nat Prod 1991, 54:196-206.
  • [9]Nshimo CM, Pezzuto JM, Kinghorn AD, Farnsworth NR: Cytotoxic constituents of Muntingia calabura leaves and stems collected in Thailand. Int J Pharmacogn 1993, 31:77-81.
  • [10]Perez-Arbelaez E: Plantas Medicinales y Venenosas de Colombia. Edited by Salazar H. Colombia: Medellin; 1975:192.
  • [11]Su BN, Jung Park E, Vigo JS, Graham JG, Cabieses F, Fong HH, Pezzuto JM, Kinghorn AD: Activity-guided isolation of the chemical constituents of Muntingia calabura using a quinone reductase induction assay. Phytochemistry 2003, 63:335-341.
  • [12]Zakaria ZA, Fatimah CA, Mat Jais AM, Zaiton H, Henie EFP, Sulaiman MR, Somchit MN, Thenamuha M, Kasthuri D: The in vitro antibacterial activity of Muntingia calabura extracts. Int J Pharmacol 2006, 2:439-442.
  • [13]Zakaria ZA, Sufian AS, Ramasamy K, Ahmat N, Sulaiman MR, Arifah AK, Zuraini A, Somchit MN: In vitro antimicrobial activity of Muntigia calabura extracts and fractions. Afr J Microbiol Res 2010, 4:304-308.
  • [14]Zakaria ZA, Mohd Nor Hazalin NA, Mohd Zaid SNH, Abdul Ghani M, Hassan MH, Gopalan HK, Sulaiman MR: Antinociceptive, anti-inflammatory and antipyretic effects of Muntingia calabura aqueous extract in animal models. J Nat Med 2007, 61:443-448.
  • [15]Zakaria ZA, Kumar GH, Mohd Zaid SNH, Abdul Ghani M, Hassan MH, Mohd Nor Hazalin NA, Khamis MM, Devi RG: Analgesic and antipyretic actions of Muntingia calabura leaves chloroform extract in animal models. Orient Pharm Exp Med 2007, 7:34-40.
  • [16]Zakaria ZA, Mohammad AM, Mohd Jamil NS, Rofiee MS, Hussain MK, Sulaiman MR, Teh LK, Salleh MZ: In vitro antiproliferative and antioxidant activities of the extracts of Muntingia calabura leaves. Am J Chin Med 2011, 39:183-200.
  • [17]Shih CD, Chen JJ, Lee HH: Activation of nitric oxide signaling pathway mediates hypotensive effect of Muntingia calabura L. (Tiliaceae) leaf extract. Am J Chin Med 2006, 34:857-872.
  • [18]Balan T, Mohd Sani MH, Suppaiah V, Mohtarrudin N, Suhaili Z, Ahmad Z, Zakaria ZA: Antiulcer activity of Muntingia calabura leaves involves the modulation of endogenous nitric oxide and nonprotein sulfhydryl compounds. Pharm Biol 2013. doi:10.3109/13880209.2013.839713
  • [19]Zakaria ZA, Sulaiman MR, Jais AM, Somchit MN, Jayaraman KV, Balakhrisnan G, Abdullah FC: The antinociceptive activity of Muntingia calabura aqueous extract and the involvement of L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in its observed activity in mice. Fundam Clin Pharmacol 2006, 20:365-372.
  • [20]Zakaria ZA, Mustapha S, Sulaiman MR, Mat Jais AM, Somchit MN, Abdullah FC: The antinociceptive action of aqueous extract from Muntingia calabura leaves: The role of opioid receptors. Med Prin Pract 2007c, 16:130-136.
  • [21]Zakaria ZA, Hassan MH, Nurul Aqmar MN, Abd Ghani M, Mohd Zaid SN, Sulaiman MR, Hanan Kumar G, Fatimah CA: Effects of various nonopioid receptor antagonist on the antinociceptive activity of Muntingia calabura extracts in mice. Methods Find Exp Clin Pharmacol 2007, 29:515-520.
  • [22]Zakaria ZA, Somchit MN, Sulaiman MR, Mat Jais AM, Fatimah CA: Effects of various receptor antagonists, pH and enzymes on Muntingia calabura antinociception in mice. Res J Pharmacol 2008, 2:31-37.
  • [23]Mohd Sani MH, Zakaria ZA, Balan T, Teh LK, Salleh MZ: Antinociceptive Activity of Methanol Extract of Muntingia calabura Leaves and the Mechanisms of Action Involved. Evid Based Compl Alt 2012. doi:10.1155/2012/890361
  • [24]Mohamad Yusof MI, Salleh MZ, Lay Kek T, Ahmat N, Nik Azmin NF, Zakaria ZA: Activity-Guided Isolation of Bioactive Constituents with Antinociceptive Activity from Muntingia calabura L. Leaves Using the Formalin Test. Evid Based Compl Alt 2013. doi:10.1155/2013/715074
  • [25]Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983, 16:109-110.
  • [26]Savegnago L, Pinto LG, Jesse CR, Alves D, Rocha JB, Nogueira CW, Zeni G: Antinociceptive properties of diphenyl diselenide: evidences for the mechanism of action. Eur J Pharmacol 2007, 555:129-138.
  • [27]Ferreira J, da Silva GL, Calixto JB: Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice. Brit J Pharmacol 2004, 141:787-794.
  • [28]Alves D, Duarte I: Involvement of ATP-sensitive K(+) channels in the peripheral antinociceptive effect induced by dipyrone. Eur J Pharmacol 2002, 444:47-52.
  • [29]De Souza MM, Pereira MA, Ardenghi JV, Mora TC, Bresciani LF, Yunes RA, Delle Monache F, Cechinel-Filho V: Filicene obtained from Adiantum cuneatum interacts with the cholinergic, dopaminergic, glutamatergic, GABAergic and tachykinergic systems to exert antinociceptive effect in mice. Pharmacol Biochem Behav 2009, 93:40-46.
  • [30]Choi SS, Han KJ, Lee HK, Han EJ, Suh HW: Possible antinociceptive mechanisms of opioid receptor antagonists in the mouse formalin test. Pharmacol Biochem Behav 2003, 75:121-124.
  • [31]Reeta K, Mediratta PK, Rathi N, Jain H, Chugh C, Sharma KK: Role of kappa and delta opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice. Regul Pept 2006, 135:85-90.
  • [32]Basbaum AI, Bushnell MC: Science of Pain. San Diego: Elsevier Inc.; 2009.
  • [33]Ji RR, Woolf CJ: Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 2001, 8:1-10.
  • [34]Khalid MH, Akhtar MN, Mohamad AS, Perimal EK, Akira A, Israf DA, Lajis N, Sulaiman MR: Antinociceptive effect of the essential oil of Zingiber zerumbet in mice: possible mechanisms. J Ethnopharmacol 2011, 137:345-351.
  • [35]Schmidt RF, Willis WD: Encyclopedia of pain. Volume 1. New York: Springer-verlag Berlin Heilberg; 2007.
  • [36]Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D: Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 2001, 411:957-962.
  • [37]Ferreira J, Triches KM, Medeiros R, Calixto JB: Mechanisms involved in the nociception produced by peripheral protein kinase C activation in mice. Pain 2005, 117:171-181.
  • [38]Vellani V, Mapplebeck S, Moriondo A, Davis JB, McNaughton PA: Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J Physiol Lond 2001, 543:813-825.
  • [39]Riley J, Boulis NM: Molecular mechanisms of pain: a basis for chronic pain and therapeutic approaches based on the cell and the gene. Clin Neurosci 2006, 53:77-97.
  • [40]Mayer S, Izydorczyk I, Reeh PW, Grubb BD: Bradykinin-induced nociceptor sensitisation to heat depends on cox-1 and cox-2 in isolated rat skin. Pain 2007, 130:14-24.
  • [41]Smith JA, Davis CL, Burgess GM: Prostaglandin E2-induced sensitization of bradykinin-evoked responses in rat dorsal root ganglion neurons is mediated by cAMP-dependent protein kinase A. Eur J Neurosci 2000, 12:3250-3258.
  • [42]Calixto JB, Cabrini DA, Ferreira J, Campos MM: Kinins in pain and inflammation. Pain 2000, 87:1-5.
  • [43]Sauer SK, Schafer D, Kress M, Reeh PW: Stimulated prostaglandin E2 release from rat skin, in vitro. Life Sci 1998, 62:2045-2055.
  • [44]Janig W: Autonomic nervous system and pain. In Science of Pain. Volume Volume 1. Edited by Basbaum AI, Bushnell MC. San Diego: Elsevier Inc; 2009.
  • [45]Bantel C, Maze M, Stone L, Wilcox G: Alpha 2-adrenergic agonists in pain treatment. In Encyclopedia of pain. 1st edition. Edited by Schmidt RF, Willis WD. New York: Springer-verlag Berlin Heilberg; 2007.
  • [46]Lavand’homme PM, Eisenach JC: Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. Pain 2003, 105:247-254.
  • [47]Carrol I, Mackey S, Gaeta R: The role of adrenergic receptors and pain: the good, the bad, and the unknown. Semin Anesth Perio M 2007, 26:17-21.
  • [48]Sawynok J, Reid A: Interactions of descending serotonergic systems with other neurotransmitters in the modulation of nociception. Behav Brain Res 1996, 73:63-68.
  • [49]Fredholm BB, Battig K, Holmen J, Nehlig A, Avartau EE: Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999, 51:83-133.
  • [50]Sawynok J: Caffeine and pain. Pain 2011, 152:726-729.
  • [51]Karlsten R, Gordh T, Post C: Local antinociceptive and hyperalgesic effects in the formalin test after peripheral administration of adenosine analogues in mice. Pharmacol Toxicol 1992, 70:434-438.
  • [52]Taiwo YO, Levine JD: Direct cutaneous hyperalgesia induced by adenosine. Neurosci 1990, 38:757-762.
  • [53]Lima FO, Souza GR, Verri WA Jr, Parada CA, Ferreira SH, Cunha FQ, Cunha TM: Direct blockade of inflammatory hypernociception by peripheral A1 adenosine receptors: involvement of the NO/cGMP/PKG/KATP signaling pathway. Pain 2010, 151:506-515.
  • [54]Wu WP, Hao JX, Halldner L, Lövdahl C, DeLander GE, Wiesenfeld-Hallin Z, Fredholm BB, Xu XJ: Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain 2005, 113:395-404.
  • [55]Nascimento FP, Macedo SJ Jr, Santos ARS: The involvement of purinergic system in pain: adenosine receptors and inosine as pharmacological tools in future treatments. In Pharmacology. Edited by Luca G. InTech; 2012. doi:10.5772/33754
  • [56]Sawynok J: Adenosine receptor activation and nociception. Eur J Pharmacol 1998, 347:1-11.
  • [57]Ito A, Kumamoto E, Takeda M, Shibata K, Sagai H, Yoshimura M: Mechanisms for ovariectomy-induced hyperalgesia and its relief by calcitonin: participation of 5–HT1A-like receptor on C-afferent terminals in substantia gelatinosa of the rat spinal cord. J Neurosci 2000, 20:6302-6308.
  • [58]Raffa RB, Codd EE: Lack of glibenclamide or TEA affinity for opioid receptors: further evidence for in vivo modulation of antinociception at K + channels. Brain Res 1994, 650:146-148.
  • [59]Ocana M, Del Pozo E, Barrios M, Robles LI, Baeyens JM: An ATP-dependent potassium channel blocker antagonizes morphine analgesia. Eur J Pharmacol 1990, 186:377-378.
  • [60]Rodrigues AR, Duarte ID: The peripheral antinociceptive effect induced by morphine is associated with ATP-sensitive K + channels. Brit J Pharmacol 2000, 129:110-114.
  • [61]Rittner HL, Machelska H, Stein C: Immune System, Pain and Analgesia. In Science of Pain. Volume 1. 1st edition. Edited by Basbaum AI, Bushnell MC. San Diego: Elsevier Inc; 2009.
  • [62]Cahill CM, Morinville A, Lee MC, Vincent JP, Collier B, Beaudet A: Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances {delta}-mediated antinociception. J Neurosci 2001, 21:7598.
  • [63]Hurley RW, Hammond DL: Contribution of endogenous enkephalins to the enhanced analgesic effects of supraspinal micro opioid receptor agonists after inflammatory injury. J Neurosci 2001, 21:2536.
  • [64]Schidmt BL, Tambeli CH, Levine JD, Gear RW: mu/cooperativity and opposing opioid effects in nucleus accumbens mediated antinociception in the rat. Eur J Neurosci 2002, 15:861-868.
  • [65]Beirith A, Santos ARS, Calixto JB, Hess SC, Messana I, Ferrari F, Yunes RA: Study of the antinociceptive action of the ethanolic extract and the triterpene 24-hydroxytormentic acid isolated from the stem bark of Ocotea suaveolens. Planta Med 1999, 65:50-55.
  • [66]Karumi Y, Onyeyili P, Ogugbuaja VO: Anti-inflammatory and antinociceptive (analgesic) properties of Momordical balsamina Linn. (Balsam apple) leaves in rats. Pak J Biol Sci 2003, 6:1515-1518.
  • [67]Musa AM, Aliyu AB, Yaro AH, Magaji MG, Hassan HS, Abdullahi MI: Preliminary phytochemical, analgesic and anti-inflammatory studies of the methanol extract of Anisopus mannii in rodents. Afr J Pharm Pharmacol 2009, 3:374-378.
  • [68]Starec M, Waitzov’a D, Elis J: Evaluation of the analgesic effect of RG-tannin using the “hot plate” and “tail flick” method in mice (in Czech). Cesk Farm 1988, 37:319-321.
  • [69]Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Gálvez J, Zarzuelo A: In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur J Immunol 2005, 35:584-592.
  • [70]Chua LS: A review on plant-based rutin extraction methods and its pharmacological activities. J Ethnopharmacol 2013, 150:805-817.
  • [71]Calixto JB, Beirith A, Ferreira J, Santos AR, Cechinel Filho V, Yunes RA: Naturally occurring antinociceptive substances from plants. Phytother Res 2000, 14:401-418.
  • [72]Bittar M, de Souza MM, Yunes RA, Lento R, Delle Monache F, Cechinel Filho V: Antinociceptive activity of I3,II8-binaringenin, a biflavonoid present in plants of the guttiferae. Planta Med 2000, 66:84-86.
  • [73]Gadotti VM, Santos ARS, Meyre-Silva C, Schmeling LO, Machado C, Liz FH, Filho VC: Antinociceptive action of the extract and the flavonoid quercitrin isolated from Bauhinia microstachya leaves. J Pharm Pharmacol 2005, 57:1345-1351.
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