Citronellol, a monoterpene alcohol, reduces nociceptive and inflammatory activities in rodents

Abstract

We describe the antinociceptive and anti-inflammatory properties of citronellol (CT) in rodents. CT, a monoterpene alcohol, is a naturally occurring monoterpene compound prevalent in essential oils of various aromatic plant species, such as Cymbopogon citratus. In mice, when evaluated against acetic-acid-induced abdominal writhing, CT (25, 50 and 100 mg/kg, i.p.) reduced (P < 0.001) the amount of writhing compared to the control group. In the formalin test, CT also significantly inhibited both the early (neurogenic pain) and the late (inflammatory pain) phases of formalin-induced licking (P < 0.001). When assessed in a thermal model of pain, CT (100 mg/kg, i.p.) caused a significant increase (P < 0.05) in the latency response on the hot-plate test. Such results were unlikely to be caused by motor abnormality. The anti-inflammatory activity of CT was investigated through carrageenan-induced pleurisy in mice. Pretreatment with CT was able to inhibit both neutrophil infiltration and the increase in TNF-α level in the exudates from carrageenan-induced pleurisy. In in vitro experiments, CT (1 and 100 μg/ml) also decreased nitric oxide production by LPS-stimulated macrophage. Together, these results indicate that CT is effective as an analgesic compound in various pain models, with its action probably mediated by the inhibition of peripheral mediators as well as central inhibitory mechanisms that could be related to its strong antioxidant effect observed in vitro.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Loeser JD, Treede RD (2008) The Kyoto protocol of IASP Basic Pain Terminology. Pain 137:473–477

    PubMed  Article  Google Scholar 

  2. 2.

    Mendonça JMD, Lyra DP, Rabelo JS, Siqueira JS, Balisa-Rocha BJ, Gimenes FRE, Bonjardim LR (2010) Analysis and detection of dental prescribing errors at Primary Health Care Units in Brazil. Pharm World Sci 32:30–35

    PubMed  Article  Google Scholar 

  3. 3.

    Batista PA, Werner MFP, Oliveira EC, Burgos L, Pereira P, Silva Brum LF, Story GM, Santos ARS (2010) The antinociceptive effect of (–)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice. J Pain 11(11):1222–1229

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Li JWH, Vederas JC (2009) Drug discovery and natural products: end of an era or an endless frontier? Science 161:325

    Google Scholar 

  5. 5.

    Butler D (2008) Crossing the valley of death. Nature 453:840–842

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Silva MAG, Aquino Neto MR, Moura BA, Sousa HL, Lavor EPH, Vasconcelos PF, Macêdo DS, De Sousa DP, Vasconcelos SMM, Sousa FCF (2009) Effects of isopulegol on pentylenetetrazol-induced convulsions in mice: possible involvement of GABAergic system and antioxidant activity. Fitoterapia 80:506–513

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Gonçalves JCR, Oliveira FS, Benedito RB, De Sousa DP, Almeida RN, Araújo DAM (2008) Antinociceptive activity of (−)-carvone. Biol Pharm Bull 31:1017–1020

    PubMed  Article  Google Scholar 

  8. 8.

    De Sousa DP (2011) Analgesic-like activity of essential oils constituents. Molecules 16:2233–2252

    PubMed  Article  Google Scholar 

  9. 9.

    Melo MS, Sena LCS, Barreto FJN, Bonjardim L, Almeida JRGS, Lima JT, De Sousa DP, Quintans-Júnior LJ (2010) Antinociceptive effect of citronellal in mice. Pharm Biol 48:411–416

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Yunes RA, Filho VC, Ferreira J, Calixto JB (2005) The use of natural products as sources of new analgesic drugs. Stud Nat Prod Chem 30:191–212

    Article  CAS  Google Scholar 

  11. 11.

    Siqueira RS, Bonjardim LR, Araujo AAS, Araújo BES, Melo MGD, Oliveira MGB, Gelain DP, Silva FA, Desantana JM, Rocha RF, Moreira JCF, Antoniolli AR, Quintans-Júnior LJ (2010) Antinociceptive activity of atranorin in mice orofacial nociception tests. Z Naturforsch C 65:551–561

    Google Scholar 

  12. 12.

    Guimarães AG, Oliveira GF, Melo MS, Cavalcanti SCH, Antoniolli AR, Bonjardim LR, Silva FA, Santos JPA, Rocha RF, Moreira JCF, Araújo AAS, Gelain DP, Quintans-Júnior LJ (2010) Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. Basic Clin Pharmacol Toxicol 107:949–957

    PubMed  Article  Google Scholar 

  13. 13.

    Quintans-Júnior LJ, Melo MS, De Sousa DP, Araújo AAS, Onofre ACS, Gelain DP, Gonçalves JCR, Araújo DAM, Almeida JRGS, Bonjardim LR (2010) Antinociceptive activity of citronellal in formalin-, capsaicin- and glutamate-induced orofacial pain in rodents and its action on nerve excitability. J Orofac Pain 24:305–312

    PubMed  Google Scholar 

  14. 14.

    Quintans-Júnior LJ, Silva DA, Siqueira JS, Araújo AAS, Barreto RSS, Bonjardim LR, DeSantana JM, De Lucca Junior W, Souza MFV, Gutierrez SJC, Barbosa-Filho JM, Santana-Filho VJ, Araújo DAM, Almeida RN (2010) Bioassay-guided evaluation of antinociceptive effect of N-Salicyloyltryptamine: a behavioral and electrophysiological approach. J Biomed Biotechnol 230745. doi: 10.1155/2010/230745

  15. 15.

    Quintans-Júnior LJ, Oliveira MGB, Santana MF, Santana MT, Guimarães AG, Siqueira JS, De Sousa DP, Almeida RN (2011) α-Terpineol reduces nociceptive behavior in mice. Pharm Biol 49:583–586

    PubMed  Article  Google Scholar 

  16. 16.

    Abegaz B, Yohannes PG, Dieter RK (1983) Constituents of the essential oil of Ethiopian Cymbopogon citratus Stapf. J Nat Prod 46:424–426

    Article  CAS  Google Scholar 

  17. 17.

    Quintans-Júnior LJ, Souza TT, Leite BS, Lessa NMN, Bonjardim LR, Santos MRV, Alves PB, Blank AF, Antoniolli AR (2008) Phytochemical screening and anticonvulsant activity of Cymbopogon winterianus Jowitt (Poaceae) leaf essential oil in rodents. Phytomedicine 15:619–624

    PubMed  Article  Google Scholar 

  18. 18.

    Tavares ES, Julião LS, Lopes D, Bizzo HR, Lage CLS, Leitão SG (2005) Análise do óleo essencial de folhas de quimiotipos de Lippia alba (Mill.) N. E. Br. (Verbenaceae) cultivados em condições semelhantes. Braz J Pharmacog 15:1–5

    Google Scholar 

  19. 19.

    De Sousa DP, Gonçalves JCR, Quintans-Júnior L, Cruz JS, Araújo DAM, Almeida RN (2006) Study of anticonvulsant effect of citronellol, a monoterpene alcohol, in rodents. Neurosci Lett 401:231–235

    PubMed  Article  Google Scholar 

  20. 20.

    Bastos JFA, Moreira IJA, Ribeiro TP, Medeiros IA, Antoniolli AR, De Sousa DP, Santos MRV (2009) Hypotensive and vasorelaxant effects of citronellol, a monoterpene alcohol, in rats. Basic Clin Pharmacol Toxicol 106:331–337

    PubMed  Article  Google Scholar 

  21. 21.

    Moreira FV, Fraga BP, Quintans-Júnior LJ, De Sousa DP, Bonjardim LR, Santos MRV(2011) Cardiovascular effects of monoterpenes: a review. Rev Bras Farmacognosia 21:764–771

    Google Scholar 

  22. 22.

    Manjavachi MN, Quintão NL, Campos MM, Deschamps IK, Yunes RA, Nunes RJ, Leal PC, Calixto JB (2009) The effects of the selective and non-peptide CXCR2 receptor antagonist SB225002 on acute and long-lasting models of nociception in mice. Eur J Pain 14(1):23–31 (Epub Mar 4)

    Google Scholar 

  23. 23.

    Tjølsen A, Berge OG, Hunskaar S, Rosland JH, Hole K (1992) The formalin test: an evaluation of the method. Pain 51:5–17

    PubMed  Article  Google Scholar 

  24. 24.

    Jacob JJ, Barthelemy CD, Tremblay EC, Colombel MC (1973) Potential usefulness of single-dose acute physical dependence on and tolerance to morphine for the evaluation of narcotic antagonists. Adv Biochem Psychopharmacol 8:299–318

    PubMed  CAS  Google Scholar 

  25. 25.

    Jacob JJ, Ramabadran K (1978) Enhancement of a nociceptive reaction by opiate antagonists in mice. Br J Pharmacol 64:91–98

    PubMed  CAS  Google Scholar 

  26. 26.

    Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JJ, Tannebaum SR (1982) Analysis of nitrate, nitrite and [15N]nitrate in biological fluid. Anal Biochem 126:131–138

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Menezes IAC, Moreira IJA, Paula JWA, Blank AF, Antoniolli AR, Quintans-Júnior LJ, Santos MRV (2010) Cardiovascular effects induced by Cymbopogon winterianus essential oil in rats: involvement of calcium channels and vagal pathway. J Pharm Pharmacol 62:215–222

    PubMed  Article  Google Scholar 

  28. 28.

    Lis-Balchin M, Patel J, Hart S (1998) Studies on the mode of action of essential oils of scented-leaf Pelargonium (Geraniaceae). Phytother Res 12:215–217

    Article  CAS  Google Scholar 

  29. 29.

    Su YW, Chao SH, Lee MH, Ou TY, Tsai YC (2010) Inhibitory effects of citronellol and geraniol on nitric oxide and prostaglandin E2 production in macrophages. Planta Med 76(15):1666–1671

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Panchagnula R, Thomas NS (2000) Biopharmaceutics and pharmacokinetics in drug research. Int J Pharm 201:131–150

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Hayes AG, Sheehan MJ, Tyers TB (1987) Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig to mu-and kappa-opioid receptor agonists. Br J Pharmacol 91:823–832

    PubMed  CAS  Google Scholar 

  32. 32.

    Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53:597–652

    PubMed  Google Scholar 

  33. 33.

    Mogil JS (2009) Animal models of pain progress and challenges. Nat Rev 10:283–294

    CAS  Google Scholar 

  34. 34.

    Raboisson P, Dallel R (2004) The orofacial formalin test. Neurosci Biobehav Rev 28:219–226

    PubMed  Article  Google Scholar 

  35. 35.

    Okuse K (2007) Pain signalling pathways: from cytokines to ion channels. Int J Biochem Cell Biol 39:490–496

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Capuano A, De Corato A, Treglia M, Tringali G, Russo CD, Navarra P (2009) Antinociceptive activity of buprenorphine and lumiracoxib in the rat orofacial formalin test: a combination analysis study. Eur J Pharmacol 605:57–62

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Hunter JC, Singh L (1994) Role of excitatory amino acid receptors in the mediation of the nociceptive response to formaline in the rat. Neurosci Lett 174:217–221

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Herrero JF, Laird JM, López-Garcia JA (2000) Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 61:169–203

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Parkhouse J, Pleuvry BJ (1979) Analgesic drug. Blackwell, Oxford, pp 1–5

    Google Scholar 

  40. 40.

    Mundey MK, Ali A, Mason R, Wilson VG (2000) Pharmacological examination of contractile responses of the guinea-pig isolated ileum produced by opioid receptor antagonists in the presence of, and following exposure to, morphine. Br J Pharmacol 131:893–902

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Peana AT, D’Aquila PS, Chessa ML, Moretti MDL, Serra G, Pippia P (2003) (–)Linalool produces antinociception in two experimental models of pain. Eur J Pharmacol 460:37–41

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Su X, Joshi SK, Kardos S, Gebhart GF (2002) Sodium channel blocking actions of the kappa-opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects. J Neurophysiol 87:1271–1279

    PubMed  CAS  Google Scholar 

  43. 43.

    Mikami T, Miyasaka K (1983) Effects of several anti-inflammatory drugs on the various parameters involved in the inflammatory response in rat carrageenin-induced pleurisy. Eur J Pharmacol 95:1–12

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Loram LC, Fuller A, Fick LG, Cartmell T, Poole S, Mitchell D (2007) Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw. J Pain 8:127–136

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Sforcin JM, Amaral JT, Fernandes A Jr, Sousa JPB, Bastos JK (2009) Lemongrass effects on IL-1β and IL-6 production by macrophages. Nat Prod Res 23:1151–1159

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Stebbing ARD (1982) Hormesis—the stimulation of growth by low levels of inhibitors. Sci Total Environ 22:213–234

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Wolff S (1989) Are radiation-induced effects hormetic? Science 245:621

    Article  Google Scholar 

  48. 48.

    Miguel MG (2011) Antioxidant and anti-inflammatory activities of essential oils. A short review. Molecules 15:9252–9287

    Article  Google Scholar 

Download references

Acknowledgments

We thank Mr. Osvaldo Andrade Santos for technical support. This work was supported by grants from the National Council of Technological and Scientific Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico/CNPq/Brazil) (grant number 305783/2010-6 and 470774/2011-8) and the Research Supporting Foundation of the State of Sergipe (Fundação de Apoio à Pesquisa e à Inovação Tecnológica do Estado de Sergipe/FAPITEC-SE) (grant number 019.203.00860/2009-6), Brazil.

Conflict of interest

The authors report no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Lucindo J. Quintans Jr..

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brito, R.G., Guimarães, A.G., Quintans, J.S.S. et al. Citronellol, a monoterpene alcohol, reduces nociceptive and inflammatory activities in rodents. J Nat Med 66, 637–644 (2012). https://doi.org/10.1007/s11418-012-0632-4

Download citation

Keywords

  • Monoterpenes
  • Citronellol
  • Pain
  • Inflammation
  • TNF-α