(−)-Linalool produces antinociception in two experimental models of pain

Abstract

Linalool is a monoterpene compound commonly found as a major component of the essential oils of several aromatic plant species, many of which are used in traditional medical systems as analgesic and anti-inflammatory remedies. We previously reported that (−)-linalool, the natural occurring enantiomer, plays a major role in the anti-inflammatory activity displayed by different essential oils, suggesting that linalool-producing species are potentially anti-inflammatory agents. In this study, the antinociceptive activity of (−)-linalool was examined in two different pain models in mice: the acetic acid-induced writhing response, a model of inflammatory pain, and the hot plate test, a model of supraspinal analgesia. Moreover, the effect of (−)-linalool on spontaneous locomotor activity (25, 50, 75 and 100 mg/kg) was evaluated. The results show that this compound induced a significant reduction of the acid-induced writhing at doses ranging from 25 to 75 mg/kg. Such effect was completely reversed both by the opioid receptor antagonist naloxone and by the unselective muscarinic receptor antagonist atropine. In the hot plate test, only the dose of 100 mg/kg of (−)-linalool resulted in a significant effect. (−)-Linalool induced a dose dependent increase of motility effects, thus ruling out the confounding influence of a possible sedative effect. The more pronounced effect of (−)-linalool on the writhing test with respect to the hot plate test is consistent with the observation that (−)-linalool possesses anti-inflammatory activity. Finally, the activation of opioidergic and cholinergic systems appears to play a crucial role in (−)-linalool-induced antinociception.

Introduction

(−)-Linalool is the natural occurring enantiomer monoterpene compound commonly found as a major volatile component of the essential oils of several aromatic plant species, many of which are used in traditional medicine to relieve symptoms and to cure a variety of acute and chronic ailments Elisabetsky et al., 1995, Lis-Balchin and Hart, 1999, Ghelardini et al., 1999, Jia et al., 1999, Perry et al., 2000, Re et al., 2000. Among these species are Salvia sclarea and Salvia desoleana. We reported that S. sclarea and S. desoleana essential oils, after systemic administration to experimental animals, showed an anti-inflammatory and a peripheral analgesic activity Moretti et al., 1997, Peana and Moretti, 2002. Moreover, we have shown that (−)-linalool and its corresponding ester linalyl acetate reduced carrageenin-induced oedema in rats at doses ranging from 25 to 75 mg/kg (Peana et al., 2002), thus suggesting a major role for (−)-linalool and its ester in the anti-inflammatory effect of these essential oils. To our knowledge, no studies on the possible antinociceptive action of (−)-linalool have been performed up to now.

The aim of this study was to evaluate the possible analgesic activity of (−)-linalool on two different pain models in mice: the acetic acid-induced writhing reaction and the hot plate test. The acetic acid-induced writhing reaction is a model of inflammatory pain, and it has long been used as a screening tool for evaluation of putative analgesic or anti-inflammatory agents Ikeda et al., 2001, Collier et al., 1968, Koster et al., 1959. The hot-plate test is considered a model of supraspinal analgesia (Forman, 1999).

Linalool is a competitive antagonist of N-methyl-d-aspartate (NMDA) receptors Elisabetsky et al., 1999, Silva Brum et al., 2001a, Silva Brum et al., 2001b and the inhibition of NMDA receptor activity produces antinociception Coderre and Van Empel, 1994, Chizh et al., 2001, partially mediated by brain opioids (Forman, 1999). Moreover, linalool possesses a weak in vitro cholinesterase inhibitory activity (Perry et al., 2000) and muscarinic neurotransmission is involved in mediating antinociception in the rat spinal cord (Naguib and Yaksh, 1997). The administration of (−)-linalool in the present study resulted in an analgesic effect, which was more pronounced in the writhing reaction test. In order to reveal the possible involvement of opioidergic and cholinergic mechanisms in this effect, we studied the effect of the opioid receptor antagonist naloxone and of the unselective muscarinic receptor antagonist atropine on (−)-linalool-induced analgesia in the writhing reaction test.

Several studies reported the ability of (−)-linalool to induce sedation in mice Buchbauer et al., 1991, Elisabetsky et al., 1995, Jirovetz et al., 1991. In order to evaluate the possible confounding influence of this effect, the locomotor activity of mice after (−)-linalool administration was evaluated.