Advertisement

Antinociceptive effect of flavonol and a few structurally related dimethoxy flavonols in mice

  • Vijaykumar SayeliEmail author
  • Jagan Nadipelly
  • Parimala Kadhirvelu
  • Binoy Varghese Cheriyan
  • Jaikumar Shanmugasundaram
  • Viswanathan Subramanian
Original Article
  • 44 Downloads

Abstract

Previous reports suggest flavonoids as potent analgesic compounds. Based on these observations, the present study investigated the antinociceptive action of flavonol, 3′, 4′-dimethoxy flavonol, 6, 3′-dimethoxy flavonol, 7, 2′-dimethoxy flavonol, and 7, 3′-dimethoxy flavonol and the possible mechanisms involved in these effects. The antinociceptive effect of the investigated compounds in doses of 25, 50, 100, and 200 mg/kg was evaluated in male Swiss albino mice using the acetic acid test, formalin-induced nociception, and hot water tail immersion test. The role of opioid, tryptaminergic, adrenergic, dopaminergic, GABAergic, and K+ATP channels in producing the antinociceptive effect was also studied using appropriate interacting agents. Treatment with flavonol and dimethoxy flavonols resulted in a significant reduction in the number of abdominal constrictions in the acetic acid test, a significant inhibition of the paw-licking/biting response time in both the phases of formalin nociception and also a significant increase in mean reaction time in the hot water tail immersion test. These observations revealed the antinociceptive effect of dimethoxy flavonols. The role of opioid, serotonergic (5HT3), and dopaminergic system was identified in the antinociceptive effect of flavonol and all dimethoxy derivatives investigated. In addition, the role of GABAergic, K+ATP channel, and α-2 adrenergic mechanisms were also observed in the antinociceptive action of some of the investigated compounds. The present study identified the antinociceptive effect of flavonol and dimethoxy flavonols in mice acting through different neuronal pathways.

Keywords

Flavonol derivatives Antinociception Neuronal mechanisms Opioid Serotonergic Dopaminergic GABAergic Adrenergic 

Notes

Acknowledgements

The support extended by Meenakshi Academy of Higher education & Research (Deemed to be University) for the study is gratefully acknowledged.

Author contributions

VSA and VSU designed the work. VSU, JN, BVC, and PK carried out the experiments, collected, and analyzed the data. VSA, VSU, and JS drafted the manuscript and revised it critically. All authors agree to be accountable for all aspects of the work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of welfare on animals

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution following the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) Government of India.

References

  1. Ahmed F, Hossain MH, Rahman AA, Shahid IZ (2006) Antinociceptive and sedative effects of the bark of Cereberaodollam Gaertn. Orient Pharm Exp Med 6:344–348CrossRefGoogle Scholar
  2. Alves DP, Tatsuo MA, Leite R, Duarte ID (2004) Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+ channels activation. Life Sci 74:2577–2591.  https://doi.org/10.1016/j.lfs.2003.10.012 CrossRefGoogle Scholar
  3. Arivudainambi R, Viswanathan S, Thirugnanasambantham P, Reddy MK, Dewan ML, Sijheer JS, Gopalakrishnan C, Vijeyasekaran V (1996) Anti-inflammatory activity of flavone and its hydroxy derivatives. A structure activity study. Ind J Pharm Sci 58:18–21Google Scholar
  4. Barasi S, Duggal KN (1985) The effect of local and systemic application of dopaminergic agents on tail flick latency in the rat. Eur J Pharmacol 117:287–294.  https://doi.org/10.1016/0014-2999(85)90001-9 CrossRefGoogle Scholar
  5. Bardin L, Laverenne J, Eschalier A (2000) Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats. Pain 86:8–11CrossRefGoogle Scholar
  6. Dickenson AH (1991) Mechanisms of the analgesic actions of opiates and opioids. Br Med Bull 47:690–702CrossRefGoogle Scholar
  7. Dubuisson D, Dennis SG (1977) The formalin test: A quantitative study of the analgesic effects of morphine, meperidine and brain stem stimulation in rats and cats. Pain 4:161–174CrossRefGoogle Scholar
  8. Ecobichon DJ (1997) The Basis of Toxicology Testing. CRC Press, New York, pp 43–86Google Scholar
  9. Farkas O, Jakus J, Heberger K (2004) Quantitative structure-antioxidant activity relationships of flavonoid compounds. Molecules 9:1079–1088.  https://doi.org/10.3390/91201079 CrossRefGoogle Scholar
  10. Filho AW, Filho VC, Olinger L (2008) Quercetin- further investigation of its antinociceptive properties and mechanism of action. Arch Pharm Res 31:713–721.  https://doi.org/10.1007/s12272-001-1217-2 CrossRefGoogle Scholar
  11. Gene RM, Segura L, AdZet T, Marin E, Iglesias J (1998) Hetrotheca inuloides: anti-inflammatory and analgesic effect. J Ethnopharmacol 60:157–162CrossRefGoogle Scholar
  12. Ghannadi A, Hajhashemi V, Jafaradabi H (2005) An investigation of the analgesic and anti-inflammatory effects of Nigella sativa seed polyphenols. J Med Food 8:488–493.  https://doi.org/10.1089/jmf.2005.8.488 CrossRefGoogle Scholar
  13. Girija K, KannapaReddy M, Viswanathan S (2002) Antinociceptive effect of synthesized dihydroxy flavones, possible mechanism. Ind J Exp Biol 40:1314–1316Google Scholar
  14. Granados-Soto V, Argulles CF, Ortiz MI (2002) The peripheral antinociceptive effect of resveratrol is associated with activation of potassium channels. Neuropharmacology 43:917–923.  https://doi.org/10.1016/S0028-3908(02)00130-2 CrossRefGoogle Scholar
  15. Hanrahan JR, Chebib M, Johnston GAR (2011) Flavonoid modulation of GABAA receptors. Br J Pharmacol 163:234–245.  https://doi.org/10.1111/j.1476-5381.2011.01228.x CrossRefGoogle Scholar
  16. Hassenbusch SJ, Gunes S, Wachsman S, Willis KD (2002) Intrathecal clonidine in the treatment of intractable pain: a phase I/II study. Pain Med 3:85–91.  https://doi.org/10.1046/j.1526-4637.2002.02014.x CrossRefGoogle Scholar
  17. Jensen TS, Yaksh TL (1984) Effects of an intrathecal dopamine agonist, apomorphine, on thermal and chemical evoked noxious responses in rats. Brain Res 296:285–293CrossRefGoogle Scholar
  18. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210.  https://doi.org/10.1038/35093019 CrossRefGoogle Scholar
  19. Jurgensen S, DalBO S, Angers P, Santos AR, Riberio-do-valle RM (2005) Involvement of 5HT2 receptors in the antinociceptive effect of Uncaria tomentosa. Pharmacol Biochem Behav 8:466–477.  https://doi.org/10.1016/j.pbb.2005.04.004 CrossRefGoogle Scholar
  20. Kamalakannan P, Vidyalakshmi K, Viswanathan S, Ramaswamy S (2014) Antinociceptive effect of certain dimethoxy flavones in mice. Eur J Pharmacol 727:148–157.  https://doi.org/10.1016/j.ejphar.2014.01.033 CrossRefGoogle Scholar
  21. Kaur R, Singh D, Chopra K (2005) Participation of alpha 2 receptor in the antinociceptive activity of quercetin. J Med Food 8:529–532.  https://doi.org/10.1089/jmf.2005.8.529 CrossRefGoogle Scholar
  22. Kernbaum S, Hauchecome J (1981) Administration of levodopa for relief of herpes Zoster pain. JAMA 246:132–134.  https://doi.org/10.1001/jama.1981.03320020024017 CrossRefGoogle Scholar
  23. Koster R, Anderson M, DeeBeer AJ (1959) Acetic acid for analgesic screening. Fed Proc 18:412–416Google Scholar
  24. Li S, Min-Hsiung P, Chin-Yu L, Di T, Yu W, Fereidoon S, Chi-Tang H (2009) Chemistry and health effects of polymethoxy flavones and hydroxylated polymethoxy flavones. J Funct Foods I:2–12CrossRefGoogle Scholar
  25. Loscalzo LM, Yow YY, Wasowski C, Chebib M, Marder M (2011) Hesperidin induces antinociceptive effect in mice and its aglycone hesperidin, binds to μ opioid receptor GIRK 1/2 currents. Pharmacol Biochem Behav 99:333–341.  https://doi.org/10.1016/j.pbb.2011.05.018 CrossRefGoogle Scholar
  26. Michael-Titus A, Bousselmame R, Costenin J (1990) Stimulation of dopamine D2 receptors induces an anesthesia involving an opioidergic but nonenkephalinergic link. Eur J Pharmacol 187:201–207CrossRefGoogle Scholar
  27. Miley DP, Abrams AA, Atkison JH, Janowsky DS (1978) Successful treatment of thalamic pain with apomorphine. Am J Psychiatry 135:1230–1232.  https://doi.org/10.1176/ajp.135.10.1230 CrossRefGoogle Scholar
  28. Millan MJ (2002) Descending control of pain. Neurobiology 66:355–474Google Scholar
  29. Muthiah NS, Viswanathan S, Thirugnanasambantham P, Reddy MK, Vijayasekaran V (1993) Antiinflammatory activity of flavone and its methoxy derivatives. A structure activity study. Ind J Pharm Sci 55:180–183Google Scholar
  30. Nadipelly J, Sayeli V, Kadhirvelu P, Shanmugasundaram J, Cheriyan BV, Subramanian V (2016) Anti-nociceptive activity of a few structurally related trimethoxy flavones and possible mechanisms involved. J Basic Clin Physiol Pharmacol 27:109–119.  https://doi.org/10.1515/jbcpp-2015-0079 CrossRefGoogle Scholar
  31. Naidu PS, Singh A, Kulkarni SK (2003) D2-dopamine receptor and α2 -adrenoreceptor mediated analgesic response of quercetin. Ind J Exp Biol 41:1400–1404Google Scholar
  32. Ocana M, Cendan CM, Cobos EJ, Entrena JM, Baeyens JM (2004) Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol 500:203–219.  https://doi.org/10.1016/j.ejphar.2004.07.026 CrossRefGoogle Scholar
  33. Ocana M, Baeyens JM (1993) Differential effects of K+ channel blockers on antinociception induced by alpha-2 adrenoceptor, GABAB and kappa-opioid receptor agonists. Br J Pharmacol 110:1049–1054CrossRefGoogle Scholar
  34. Pan YZ, Li DP, Pan HL (2002) Inhibition of glutaminergic synaptic input to spinal lamina II (o) neurons by presynaptic α (2)- adrenergic receptors. J Neurophysiol 87:1938–1947.  https://doi.org/10.1152/jn.00575.2001 CrossRefGoogle Scholar
  35. Pietrovski EF, Kelson AR, Valdir AF, Katiuscia R, Maria Consuelo AM, Santos ARS (2006) Antinociceptive properties of the ethanolic extract and of the triterpene 3β, 6β, 16β-trihidroxilup-20(29)-ene obtained from the flowers of Combretum leprosum in mice. Pharmacol Biochem Behav 83:90–99.  https://doi.org/10.1016/j.pbb.2005.12.010 CrossRefGoogle Scholar
  36. Rajendran NN, Thirugnanasabantham P, Viswanathan S, Parvathavarthini S, Ramaswamy S (2000) Antinociceptive pattern of flavone and its mechanism as tested by formalin assay. Ind J Exp Biol 38:182–185Google Scholar
  37. Rauck RL, Eisenach JC, Jackson K, Young LD, Southern J (1993) Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology 79:1163–1169CrossRefGoogle Scholar
  38. Rice-Evans CA, Miller JM, Paganga G (1996) Structure-antioxidant activity relationship of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956.  https://doi.org/10.1016/0891-5849(95)02227-9 CrossRefGoogle Scholar
  39. Robles LI, Barrios M, Del Pozo E, Doral A, Baeyens M (1996) Effect of K+ channel blockers and openers on antinociception induced by agonists of 5HT1A receptors. Eur J Pharmacol 295:181–188.  https://doi.org/10.1016/0014-2999(95)00643-5 CrossRefGoogle Scholar
  40. Rodrigues AL, Dasilva GL, Mateussi AS, Fernandes ES, Miquel OG, Yunes RA, Calixto JB, Santos AR (2002) Involvement of monoaminergic system in the antidepressant–like effect of the hydroalcoholic extract of Siphocampylusverticilatus. Life Sci 70:1347–1358CrossRefGoogle Scholar
  41. Sari MHM, Souza ACG, Rosa SG, Souza D, Dorneles Rodrigues OE, Wayne Nogueira C (2014) Contribution of dopaminergic and adenosinergic systems in the antinociceptive effect of P-chloro-selenosteroid. Eur J Pharmacol 725:79–86CrossRefGoogle Scholar
  42. Sasaki M, Ishizaki K, Obato H, Goto F (2001) Effects of 5 HT2 and 5 HT3 receptors on the modulation of nociceptive transmission in rat spinal cord according to the formalin test. Eur J Pharmacol 424:45–52CrossRefGoogle Scholar
  43. Sewell RDE, Spencer PSJ (1976) Antinociceptive activity of narcotic agonists and partial agonist analgesics and other agents in tail immersion test in mice and rats. J Neuropharm 15:683–688CrossRefGoogle Scholar
  44. Thirugnanasambantham P, Viswanathan S, Kannappa Reddy M, Ramachandran S, Kameswaran L (1985) Analgesic activity of certain bioflavonoids. Ind J Pharm Sci 47:230–231Google Scholar
  45. Thirugnanasambantham P, Viswanathan S, Krishnamoorthy V, Ramachandran S, Mythiraye CI, Kameswaran L (1990) Analgesic activity of certain flavones derivatives. A structure activity study. J Ethnopharmacol 28:207–214CrossRefGoogle Scholar
  46. Thirugnanasambantham P, Viswanathan S, Ramaswamy S, Krishnamoorthy V, Mythirayee CI, Kameswaran L (1993) Analgesic activity of certain flavone derivatives. A structure activity study. Clin Expl Pharmacol Physiol 20:59–63CrossRefGoogle Scholar
  47. Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K (1992) The formalin test: an evaluation of the method. Pain 51:5–17CrossRefGoogle Scholar
  48. Tjolsen A, Hole K (1997) Animal models of analgesia. In: Dickenson A, Besson J. (eds) The Pharmacology of Pain, Springer, Berlin, vol 130, pp 1–20Google Scholar
  49. Umamaheswari S, Viswanathan S, Sathiyasekaran BWC, Parvathavarthini S, Ramaswamy S (2006) Antinociceptive activity of certain dihydroxy flavones. Ind J Pharm Sci 68:749–753CrossRefGoogle Scholar
  50. Venkataramanan PE, Parvathavarthini S, Viswanathan S (2000) Role of ATP sensitive potassium channel on 7-hydroxy flavone induced antinociception and possible association with changes in glycaemic status. Ind J Exp Biol 38:1172–1174Google Scholar
  51. Vidyalakshmi K, Kamalakannan P, Viswanathan S, Ramaswamy S (2010) Antinociceptive effect of certain dihydroxy flavones in mice. Pharmacol Biochem Behav 96:1–6CrossRefGoogle Scholar
  52. Viswanathan S, Thirugnanasambantham P, Reddy MK, Kameswaran L (1984) Gossypin induced analgesia in mice. Eur J Pharmacol 98:289–291CrossRefGoogle Scholar
  53. Viswanathan S, Thirugnanasambantham P, Ramaswamy S, Bapna JS (1993) A study on the role of cholinergic and gamma amino butyric acid systems in the antinociceptive effect of gossypin. Clin Exp Pharmacol and Physiol 20:193–196CrossRefGoogle Scholar
  54. Zellhofer HU, Mohler H, Di-Lio A (2009) GABAergic analgesia; new insights from mutant mice and subtype-selective agonists. Trends Pharmacol Sci 30:397–402.  https://doi.org/10.1016/j.tips.2009.05.007 CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PharmacologyMamata Medical CollegeKhammamIndia
  2. 2.Department of Pharmacology, Faculty of MedicineTexila American UniversityGeorgetownGuyana
  3. 3.Department of PharmacologyMeenakshi Medical College and Research Institute, Meenakshi Academy of Higher Education and Research (Deemed To Be University)KanchipuramIndia
  4. 4.Department of Pharmaceutical ChemistryVISTAS, VELS School of Pharmaceutical SciencesChennaiIndia

Personalised recommendations