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

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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.

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Generally recognized as safe






Central nervous system






Periaqueductal gray


Nucleus raphe magnus


Locus coeruleus




Rostroventromedial medullary


Acid-sensing ion channels


Vaniloid receptor family




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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.

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Correspondence to Lucindo J. Quintans-Júnior.

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Nascimento, S.S., Camargo, E.A., DeSantana, J.M. et al. Linalool and linalool complexed in β-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia. Naunyn-Schmiedeberg's Arch Pharmacol 387, 935–942 (2014).

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