Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 387, Issue 10, pp 935–942 | Cite as

Linalool and linalool complexed in β-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia

  • Simone S. Nascimento
  • Enilton A. Camargo
  • Josimari M. DeSantana
  • Adriano A. S. Araújo
  • Paula P. Menezes
  • Waldecy Lucca-Júnior
  • Ricardo L. C. Albuquerque-Júnior
  • Leonardo R. Bonjardim
  • Lucindo J. Quintans-JúniorEmail author
Original Article


The analgesic activity of (−)-linalool (LIN), a monoterpene present in essential oils of Lamiaceae species, has been previously demonstrated in rodents. However, its possible use in the treatment of fibromyalgia (FM) was never demonstrated. Additionally, as a short half-life is a limitation for the LIN medicinal application, the employment of drug delivery systems has been used to improve pharmaceutical properties of this compound. We investigated the anti-nociceptive effect of LIN, isolated or in β-cyclodextrin complex (LIN–CD), in an animal model of chronic non-inflammatory muscle pain (a FM animal model), as well as its effect on the central nervous system (CNS). Male Swiss mice were subjected to two injections of acidic saline (pH 4; 20 μL/gastrocnemius) and were treated on alternate days, with LIN–CD (25 mg/kg, p.o.), LIN (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.), or vehicle (neutral saline). After 60 min, they were screened for mechanical hyperalgesia (von Frey), motor coordination (rotarod), and muscle strength (grip strength meter) for 27 days. The CNS areas involved in the anti-hyperalgesic activity were evaluated by immunofluorescence. LIN or LIN–CD produced a significant reduction (p < 0.001) of mechanical hyperalgesia on chronic non-inflammatory muscle pain model, which remained for 24 h only in LIN–CD, and these compounds significantly (p < 0.05) activated neurons of the locus coeruleus, nucleus raphe magnus, and periaqueductal gray areas. So, our results suggest that LIN–CD improved analgesic profile of LIN, with a probable involvement of descending pain pathways and the anti-nociceptive effect of linalool in an animal model of chronic non-inflammatory muscle pain. So far, only the investigations in animal models of inflammatory pain and supraspinatus were published.


Linalool β-Cyclodextrin Chronic muscle pain Fibromyalgia Fos protein 





Generally recognized as safe






Central nervous system






Periaqueductal gray


Nucleus raphe magnus


Locus coeruleus




Rostroventromedial medullary


Acid-sensing ion channels


Vaniloid receptor family





We thank Mr. Osvaldo Andrade Santos for the technical support. This work was supported by grants from FAPITEC-SE/Brazil (grants 01790/2011-8/PRONEM/2011 and PPSUS-FAPITEC) and CNPq/Brazil (grants 305783/2010-6, 470774/2011-8, and 407436/2013-8). We thank teacher Abilio Borghi for the grammar review of the manuscript and Renan G. Brito for support in immunofluorescence assay.

Conflict of interest

The authors report no conflict of interest.


  1. Batista PA, Werner MFP, Oliveira EC, Burgos L, Pereira P, Brum LFS, Santos ARS (2008) Evidence for the involvement of ionotropic glutamatergic receptors on the antinociceptive effect of (−)-linalool in mice. Neurosci Lett 440:299–303PubMedCrossRefGoogle Scholar
  2. Bendtsen L, Nørregaard J, Jensen R, Olesen J (1997) Evidence of qualitatively altered nociception in patients with fibromyalgia. Arthritis Rheum 40:98–102PubMedCrossRefGoogle Scholar
  3. Berliocchi L, Russo R, Levato A, Fratto V, Bagetta G, Sakurada S, Sakurada T, Mercuri NB, Corasaniti MT (2009) (−)‐Linalool attenuates allodynia in neuropathic pain induced by spinal nerve ligation in C57/Bl6 mice. Int Rev Neurobiol 85:221–235PubMedCrossRefGoogle Scholar
  4. Brito RG, Santos PL, Prado DS, Santana MT, Araújo AA, Bonjardim LR, Santos MR, de Lucca JW, Oliveira AP, Quintans-Júnior LJ (2013) Citronellol reduces orofacial nociceptive behaviour in mice—evidence of involvement of retrosplenial cortex and periaqueductal grey areas. Basic Clin Pharmacol Toxicol 112(4):215–221PubMedCrossRefGoogle Scholar
  5. Brum LS, Emanuelli T, Souza D, Elisabetsky E (2001) Effects of linalool on glutamate release and uptake in mouse cortical synaptosomes. Neurochem Res 26:191–194CrossRefGoogle Scholar
  6. Burmeister SS, Mangiamele LA, Lebonville CL (2008) Acoustic modulation of immediate early gene expression in the auditory midbrain of female túngara frogs. Brain Res 1190:105–114PubMedCrossRefGoogle Scholar
  7. Chizh BA, Headley PM, Tzschentke TM (2001) NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci 22:636–642PubMedCrossRefGoogle Scholar
  8. Cunha T, Verri W Jr, Vivancos G, Moreira I, Reis S, Parada C, Cunha F, Ferreira S (2004) An electronic pressure-meter nociception paw test for mice. Braz J Med Biol Res 37:401–407PubMedCrossRefGoogle Scholar
  9. Dadabhoy D, Clauw DJ (2005) Fibromyalgia: progress in diagnosis and treatment. Curr Pain Headache Rep 9:399–404PubMedCrossRefGoogle Scholar
  10. DeSantana JM, Da Silva L, De Resende M, Sluka K (2009) Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats. Neuroscience 163:1233–1241PubMedCrossRefPubMedCentralGoogle Scholar
  11. DeSantana JM, da Cruz KM, Sluka KA (2013). Animal models of fibromyalgia. Arthritis Res Ther 15(6):222Google Scholar
  12. Guimarães APC, Prado WA (1999) Pharmacological evidence for a periaqueductal gray–nucleus raphe magnus connection mediating the antinociception induced by microinjecting carbachol into the dorsal periaqueductal gray of rats. Brain Res 827:152–159PubMedCrossRefGoogle Scholar
  13. Guimarães AG, Xavier MA, de Santana MT, Camargo EA, Santos CA, Brito FA, Barreto EO, Cavalcanti SC, Antoniolli AR, Oliveira RC, Quintans-Júnior LJ (2012) Carvacrol attenuates mechanical hypernociception and inflammatory response. Naunyn Schmiedebergs Arch Pharmacol 385:253–263PubMedCrossRefGoogle Scholar
  14. Guimarães AG, Quintans JSS, Quintans Júnior LJ (2013) Monoterpenes with analgesic activity—a systematic review. Phytother Res 27:1–15PubMedCrossRefGoogle Scholar
  15. Guimarães AG, Serafini MR, Quintans Júnior LJ (2014) Terpenes and derivatives as a new perspective for pain treatment: a patent review. Expert Opin Ther Pat 24:243–265PubMedCrossRefGoogle Scholar
  16. Leal-Cardoso JH, da Silva-Alves KS, Ferreira-da-Silva FW, dos Santos-Nascimento T, Joca HC, de Macedo FHP, de Albuquerque-Neto PM, Magalhães PJC, Lahlou S, Cruz JS (2010) Linalool blocks excitability in peripheral nerves and voltage-dependent Na < sup > +</sup > current in dissociated dorsal root ganglia neurons. Eur J Pharmacol 645:86–93PubMedCrossRefGoogle Scholar
  17. Liapi C, Anifantis G, Chinou I, Kourounakis AP, Theodosopoulos S, Galanopoulou P (2007) Antinociceptive properties of 1, 8-cineole and β-pinene, from the essential oil of Eucalyptus camaldulensis leaves, in rodents. Planta Med 73:1247–1254PubMedCrossRefGoogle Scholar
  18. Marques HMC (2010) A review on cyclodextrin encapsulation of essential oils and volatiles. Flavour and Fragr J 25:313–326CrossRefGoogle Scholar
  19. Marreto RN, Almeida EE, Alves PB, Niculau ES, Nunes RS, Matos CR, Araújo AA (2008) Thermal analysis and gas chromatography coupled mass spectrometry analyses of hydroxypropyl-β-cyclodextrin inclusion complex containing Lippia gracilis essential oil. Thermochim Acta 475:53–58CrossRefGoogle Scholar
  20. Menezes PP, Serafini MR, Santana BV, Nunes RS, Quintans-Júnior LJ, Silva GF, Medeiros IA, Marchioro M, Fraga BP, Santos MR (2012) Solid-state β-cyclodextrin complexes containing geraniol. Thermochim Acta 548:45–50CrossRefGoogle Scholar
  21. Menezes PP, Serafini MR, Quintans-Júnior LJ, Silva GF, Oliveira JF, Carvalho JCC, Matos JR, Hãdãruga DI, Araujo AAS (2014) Inclusion complex of (−)-linalool and β-cyclodextrin. J Therm Anal Calorim 115:2429–2437CrossRefGoogle Scholar
  22. Meyer O, Tilson H, Byrd W, Riley M (1979) A method for the routine assessment of fore- and hindlimb grip strength of rats and mice. Neurobehav Toxicol 1:233PubMedGoogle Scholar
  23. Nascimento S, DeSantana JM, Nampo FK, Ribeiro ÊAN, da Silva DL, Araújo-Júnior JX, da Silva Almeida JRG, Bonjardim LR, de Souza Araújo AA, Quintans-Júnior LJ (2013) Efficacy and safety of medicinal plants or related natural products for fibromyalgia: a systematic review. Evidence-Based Complementary and Alternative Medicine 2013Google Scholar
  24. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. San Diego, Academic PressGoogle Scholar
  25. Peana AT, D’Aquila PS, Chessa ML, Moretti MD, Serra G, Pippia P (2003) (−)-Linalool produces antinociception in two experimental models of pain. Eur J Pharmacol 460:37–41PubMedCrossRefGoogle Scholar
  26. Peana AT, Graziella De Montis M, Sechi S, Sircana G, D’Aquila PS, Pippia P (2004) Effects of (−)-linalool in the acute hyperalgesia induced by carrageenan, l-glutamate and prostaglandin E < sub > 2</sub> Eur J Pharmacol 497:279–284PubMedCrossRefGoogle Scholar
  27. Pillemer SR, Bradley LA, Crofford LJ, Moldofsky H, Chrousos GP (2005) The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum 40:1928–1939CrossRefGoogle Scholar
  28. Quintans JSS, Menezes PP, Santos MRV, Bonjardim LR, Almeida JRGS, Gelain DP, Araujo AAS, Quintans-Júnior LJ (2013) Improvement of p-cymene antinociceptive and anti-inflammatory effects by inclusion in β-cyclodextrin. Phytomedicine 20:436–440CrossRefGoogle Scholar
  29. Quintans JSS, Antoniolli AR, Almeida JR, Santana-Filho VJ, Quintans-Júnior LJ (2014) Neuropathic pain models—a systematic review. Basic Clin Pharmacol Toxicol 114:442–450PubMedCrossRefGoogle Scholar
  30. Quintans-Júnior LJ, Santana MT, Melo MS, de Sousa DP, Santos IS, Siqueira RS, Lima TC, Silveira GO, Antoniolli AR, Ribeiro LA (2010) Antinociceptive and anti-inflammatory effects of Costus spicatus in experimental animals. Pharm Biol 48:1097–1102PubMedCrossRefGoogle Scholar
  31. Quintans-Júnior LJ, Barreto RS, Menezes PP, Almeida JR, Viana AF, Oliveira RC, Oliveira AP, Gelain DP, de Lucca JW, Araújo AAS (2013) β-Cyclodextrin-complexed (−)-linalool produces antinociceptive effect superior to that of (−)-linalool in experimental pain protocols. Basic Clin Pharmacol Toxicol 113(3):167–172PubMedCrossRefGoogle Scholar
  32. Ren K, Williams GM, Hylden JL, Ruda M, Dubner R (1992) The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats. Eur J Pharmacol 219:235–243PubMedCrossRefGoogle Scholar
  33. Sakurada T, Mizoguchi H, Kuwahata H, Katsuyama S, Komatsu T, Morrone LA, Corasaniti MT, Bagetta G, Sakurada S (2011) Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism. Pharmacol Biochem Behav 97:436–443PubMedCrossRefGoogle Scholar
  34. Serafini MR, Menezes PP, Costa LP, Lima CM, Quintans-Júnior LJ, Cardoso JC, Matos J, Soares-Sobrinho L, Grangeiro-Júnior S, Nunes PS, Bonjadim LR, Araújo AAS (2012) Interaction of p-cymene with β-cyclodextrin. J Therm Anal Calorim 109:951–955CrossRefGoogle Scholar
  35. Siqueira Lima PS, Araújo AA, Lucchese AM, Quintans JS, Menezes PP, Alves PB, Lucca Júnior W, Santos MR, Bonjardim LR, Quintans Júnior LJ (2014) β-Cyclodextrin complex containing Lippia grata leaf essential oil reduces orofacial nociception in mice—evidence of possible involvement of descending inhibitory pain modulation pathway. Basic Clin Pharmacol Toxicol 114:188–196PubMedCrossRefGoogle Scholar
  36. Sluka K, Kalra A, Moore S (2001) Unilateral intramuscular injections of acidic saline produce a bilateral, long‐lasting hyperalgesia. Muscle Nerve 24:37–46PubMedCrossRefGoogle Scholar
  37. Sluka KA, Price MP, Breese NM, Stucky CL, Wemmie JA, Welsh MJ (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 106:229–239PubMedCrossRefGoogle Scholar
  38. Sluka KA, Winter OC, Wemmie JA (2009) Acid-sensing ion channels: a new target for pain and CNS diseases. Curr Opin Drug Discov Devel 12:693PubMedPubMedCentralGoogle Scholar
  39. Staud R (2006) Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther 8:208PubMedCrossRefPubMedCentralGoogle Scholar
  40. Venâncio AM, Marchioro M, Estavam CS, Melo MS, Santana MT, Onofre AS, Guimarães AG, Oliveira MG, Alves PB, Pimentel HC, Quintans-Júnior LJ (2011) Ocimum basilicum leaf essential oil and (−)-linalool reduce orofacial nociception in rodents: a behavioral and electrophysiological approach. Revista Brasileira de Farmacognosia 21:1043–1051CrossRefGoogle Scholar
  41. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB (2010) The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 62:600–610CrossRefGoogle Scholar
  42. Yokoyama T, Maeda Y, Audette KM, Sluka KA (2007) Pregabalin reduces muscle and cutaneous hyperalgesia in two models of chronic muscle pain in rats. J Pain 8:422–429PubMedCrossRefGoogle Scholar
  43. Zubrzycka M, Szemraj J, Janecka A (2011) Effect of tooth pulp and periaqueductal central gray stimulation on the expression of genes encoding the selected neuropeptides and opioid receptors in the mesencephalon, hypothalamus and thalamus in rats. Brain Res 1382:19–28PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Simone S. Nascimento
    • 1
  • Enilton A. Camargo
    • 1
  • Josimari M. DeSantana
    • 2
  • Adriano A. S. Araújo
    • 3
  • Paula P. Menezes
    • 3
  • Waldecy Lucca-Júnior
    • 4
  • Ricardo L. C. Albuquerque-Júnior
    • 5
  • Leonardo R. Bonjardim
    • 6
  • Lucindo J. Quintans-Júnior
    • 1
    Email author
  1. 1.Department of PhysiologyFederal University of Sergipe (DFS/UFS)São CristóvãoBrazil
  2. 2.Department of Physical TherapyFederal University of Sergipe (DFS/UFS)AracajuBrazil
  3. 3.Department of PharmacyFederal University of Sergipe (DFS/UFS)AracajuBrazil
  4. 4.Department of MorphologyFederal University of Sergipe (DFS/UFS)AracajuBrazil
  5. 5.Institute of Technology and ResearchTiradentes UniversityAracajuBrazil
  6. 6.Department of Biological Sciences, Bauru School of DentistryUniversity of São PauloSão PauloBrazil

Personalised recommendations