Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism
Research Highlights
► BEO-induced antinociceptive may be mediated through peripheral opioid receptors. ► Linalool-induced antinociceptive may be mediated through peripheral opioid receptors. ► Antinociception induced by morphine was enhanced by the combined injection of BEO. ► Antinociception induced by morphine was enhanced by the combined injection of linalool.
Introduction
The essential oil of bergamot (BEO; Citrus bergamia, Risso) is one of the most common essential oil and most familiar to the general public. BEO is obtained by cold pressing of the epicarp and in part of the mesocarp of the fresh fruit of bergamot. BEO consists of a volatile fraction (93–96%) and a non volatile fraction (4–7%); the former fraction contains monoterpene and sesquiterpene hydrocarbons and oxygenated derivatives such as linalool and linalyl acetate, and the latter fraction contains waxes, polymethoxylated flavones, coumarins and psoralens such as bergamottin and bergapten (Mondello et al., 1993, Dugo et al., 2000). Recently, BEO has been shown to reduce neuronal damage caused by excitotoxic stimuli (Corasaniti et al., 2007). (−) Linalool is the natural occurring enantiomer of the monoterpene compound found in the essential oil extracted from aromatic plants such as sauge, lavender, rose wood, thyme and bergamot. As previously reported (Peana et al., 2002, Peana et al., 2003, Peana et al., 2004), (−) linalool administration produced anti-inflammatory and antinociceptive activities in several behavioral assays. However, the antinociceptive efficacy of intraplantar BEO and linalool on capsaicin-induced nociceptive response is unknown.
The capsaicin (8-methly-N-vanillyl-6-noneamide) test is widely used as a model of pain in mice (Sakurada et al., 1992), rats (Pelissier et al., 2002) and humans (Hughes et al., 2002). We previously reported that subcutaneous (s.c.) injection of capsaicin into the hindpaw produced a short-lasting paw-licking/biting response, which was dose-dependently inhibited by intrathecally (i.t.) administered morphine (Sakurada et al., 1994). Activation of primary afferent nociceptors by capsaicin causes the release of nociceptive transmitters, substance P and glutamate from the dorsal spinal cord in vivo and in vitro (Gamse et al., 1979, Ueda et al., 1993, Sorkin and McAdoo, 1993). In addition, it has been shown that capsaicin excites the C-fiber population of nociceptive afferents through transient receptor potential vanilloid type-1 (TRPV-1) receptors located in C-fiber type nociceptors (Di Marzo et al., 2002, Szallasi et al., 2007).
In this study, the effects of BEO on capsaicin-evoked acute pain were investigated in comparison with linalool. In addition, here intraplantar injection BEO and linalool were tested for (1) production of antinociception in a capsaicin pain model, (2) assessment of the involvement of peripheral opioid system, and (3) modulation of the antinociceptive effect of morphine.
Section snippets
Animals
Male ddY (SD) mice (Shizuoka Laboratory Center, Japan) weighing 22–26 g, at the time of testing, were used in these experiments. The mice were individually housed in a colony maintained in a controlled environment (12 h light/dark cycle, room temperature 23 °C, 50–60% relative humidity).
The animals had unlimited access to food pellets and water. All behavioral experiments took place during the light period between 10:00 and 17:00 h in a quiet room. The animals belonging to the various treatment
Effects of BEO, linalool and linalyl acetate injected into the hindpaw
The effects of BEO, linalool and linalyl acetate were examined when injected into the hindpaw plantar surface in mice. Licking/biting behavior after intraplantar injection of BEO (5 and 10 μg/paw), linalool (2.5, 5.0 and 10 μg/paw) linalyl acetate (10 and 20 μg/paw) and jojoba wax was not statistically different when compared with saline-treated group (Table 1). Only the maximum concentration of BEO (20 μg/paw) produced a significant nociceptive response, which peaked at 5–10 min and had almost
Discussion
The effects of a common aromatic essential oil, e.g. BEO, and of its main oxygenated monoterpenes, linalool and linalyl acetate, were investigated in a mouse capsaicin pain model. Intraplantar injection of BEO, linalool or linalyl acetate reduced behavioral signs of capsaicin-induced nociception in a dose-dependent manner. BEO and linalool injected into the contralateral paw were not antinociceptive at a sufficient antinociceptive dose used in the ipsilateral paw. This finding suggests that
Acknowledgements
This work was supported by The Science Research Promotion Fund from The Promotion and Mutual Aid Corporation for Private Schools of Japan, a Grant-in-Aid for Science Research (C) (KAKENHI 16590058 and 17590065) from the Japan Society for the Promotion of Science, and a Grant-in-Aid for High Technology Research Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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