Profile of spinal and supra-spinal antinociception of (−)-linalool
Introduction
(−)-Linalool is the naturally occurring enantiomer monoterpene compound commonly found as a major volatile component of the essential oils of several aromatic plant species. The effects produced by this compound include a significant inhibition of carrageenin-induced oedema in rats (Peana et al., 2002) and a reduction in acetic acid-induced writhing in mice at doses ranging from 25 to 75 mg/kg. Antinociception exerted by (−)-linalool in the writhing test appears to depend both on opioidergic and on cholinergic neurotransmission, since (−)-linalool effect was completely antagonised by the opioid receptor antagonist naloxone and by the unselective muscarinic cholinergic receptor antagonist atropine (Peana et al., 2003). It was also reported that linalool modulates glutamate activation expression in vitro (competitive antagonism of l-[3H]glutamate binding) and in vivo (delayed subcutaneous N-methyl-d-aspartate (NMDA)-induced convulsions and blockade of intracerebroventricular quinolinic acid-induced convulsions) Silva Brum et al., 2001a, Silva Brum et al., 2001b. Moreover, other authors have reported that linalool modifies the nicotinic receptor-ion channel kinetics at the mouse neuromuscular junction (Re et al., 2000), and possesses a local anaesthetic activity (Ghelardini et al., 1999), a spasmolitic effect (Lis-Balchin and Hart, 1999) and a weak in vitro cholinesterase inhibitory activity (Perry et al., 2000). Linalool also has been shown to possess antioxidant properties (Celik and Ozkaya, 2002).
To further characterise the antinociceptive profile of (−)-linalool, we have examined in the present study the effects of systemic administration of (−)-linalool on thermal reactivity assessed by the hot-plate test in mice and on pain behaviour produced by an injection of a low concentration (1%) of formalin in rats. The hot-plate model is a nociception test very sensitive to opioids, used as a means of assessing acute antinociceptive activity depending upon spinal and supra-spinal mechanisms. The formalin test is widely used as a model of acute inflammatory pain. Formalin injection activates peripheral sensory nerves and produces pain responses that involve ongoing peripheral activity and peripheral and central sensitisation. Pain behaviours are related to formalin concentration and different mechanisms are involved at low and high concentrations. Thus, at low concentrations (<2%), there is a predominant activity of capsaicin-sensitive neurogenic components, while at high concentrations (5%), there is the additional involvement of more complex inflammatory elements and a peripheral release of glutamate (Sawynok and Reid, 2002).
Furthermore, to determine the possible participation of the cholinergic, opioidergic and dopaminergic systems, previously shown to be involved in the modulation of nociception, we tested the effects of atropine, pirenzepine, a selective muscarinic M1 receptor antagonist, naloxone, sulpiride, a selective dopamine D2 receptor antagonist and (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH-23390), a selective dopamine D1 receptor antagonist, on (−)-linalool-induced antinociception both in the 1% formalin test and in the hot-plate test. Moreover, since K+ channels play an important role in pain modulation, the effects of the ATP-sensitive K+ channel inhibitor glibenclamide were examined on (−)-linalool-induced antinociception in the 1% formalin model and in hot-plate tests.
Section snippets
Materials and methods
The present study was carried out in accordance to the Italian law, which allows experiments on laboratory animals only after submission of a research project to the competent authorities, and in accordance to the “Principles of Laboratory Animal Care” (NIH publication no. 85-23, revised 1985).
Effect of (−)-linalool on the hot-plate test
ANOVA revealed a significant main effect of treatment (F(2,96)=6.09, P=0.0032) and time (F(2,192)=6.47, P=0.0019) but not a significant interaction between the two factors. LSD test, performed to investigate the differences between the groups, has shown a significant increase in latency time with respect to controls in animals treated with (−)-linalool at 100 mg/kg (P=0.0051) and 150 mg/kg (P=0.0030). No significant differences between the groups treated with 100 and 150 mg/kg (−)-linalool were
Discussion
The present results show the efficacy of (−)-linalool in antagonising different pain responses generated either by the exposure to a thermal nociceptive stimulus applied in the hot-plate test or by a tissue injure produced by formalin injection (Haley et al., 1990). The antinociceptive effects of (−)-linalool occurred at doses that did not produce any visible modification of the animal's gross behaviour.
In the present study, a significant antinociceptive response in the hot-plate test was
Acknowledgements
The authors wish to thank Dr. M. Loredana Chessa, Ms. S. Sechi and Ms. Giulia Chessa for their excellent technical assistance.
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