This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalininduced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO-and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.The essential oil of bergamot (BEO; Citrus bergamia Risso) is one of the most commonly used essential oils and is familiar to most of the general public. BEO is obtained by cold pressing of the epicarp and part of the mesocarp of the fresh bergamot fruit. BEO consists of a volatile (93-96%) and a nonvolatile fraction (4-7%); the former contains monoterpene and sesquiterpene hydrocarbons and oxygenated derivatives such as linalool and linalyl acetate, while the latter fraction contains waxes, polymethoxylated flavones, coumarins, and psoralens such as bergamottin and bergapten (6,14). BEO has been reported to minimize symptoms of stress-induced anxiety and mild mood disorders, as well as cancer pain, however the mechanistic basis for its use in such applications awaits discovery (1). A previous in vitro study showed that BEO reduced neuronal damage caused by excitotoxic stimuli (5), and significantly increased the extracellular levels of the inhibitory amino acid neurotransmitter gamma-aminobutyric acid (GABA) in rat hippocampus (15). Linalool is a monoterpene compound and is the main volatile component of the essential oils of various plants, including BEO. It has previously been reported that linalool administration produced antibacterial, anticonvulsant, and anti-inflammatory effects, as well as showing antinociceptive activity in several behavioral assays (2)(3)(4)(16)(17)(18)(19)(20). Furthermore, linalool can significantly reduce both mor-

Linalool is the principal component of many essential oils known to possess biological activities. We previously reported that intraplantar injection of linalool reduces the nociceptive response as assayed by the capsaicin test. In this study, we sought to determine whether intraplantar injection of linalool could influence the induction of acute pain (allodynia and hyperalgesia) by paclitaxel in mice. Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it sometimes induces moderate to severe acute pain. Paclitaxel administered intraperitoneally as a single dose of 5, 10 or 20 mg/kg produced mechanical allodynia and hyperalgesia in mice. Paclitaxel-induced mechanical allodynia and hyperalgesia began 1 day after administration of paclitaxel and resolved within 7 days. Linalool injected into the hindpaw caused a significant reduction in paclitaxel-induced mechanical allodynia and hyperalgesia. Pretreatment with naloxone hydrochloride, an opioid receptor antagonist, or naloxone methiodide, a peripherally acting μ-opioid receptor-preferring antagonist, significantly reversed linalool-induced antiallodynia and antihyperalgesia. Our results provide evidence for the involvement of peripheral opioids in antiallodynia and antihyperalgesia induced by linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing paclitaxel-induced mechanical allodynia and hyperalgesia.The major classes of antineoplastic agents-the vinca alkaloids, taxanes, bortezomib and platinum-derived compounds-are associated with the development of dose-limiting neuropathic pain (12, 32). Paclitaxel is a taxane chemotherapeutic commonly used for the treatment of solid tumors and ovarian and breast cancers. Paclitaxel acts as an antimitotic by stabilizing microtubules against disassembly, thus inhibiting the cell cycle in late mitosis and ultimately inducing apoptosis (30). Peripheral neuropathy sometimes occurs as a side-effect of chemotherapeutic treatment with paclitaxel and often manifests as bilateral pain in the extremities in a stocking and glove-type distribution (5). This pain can greatly reduce patients' quality of life and affect activities of daily living. Furthermore, paclitaxel therapy often results in acute pain (16,21). Acute pain begins 1-3 days after the commencement of treatment with paclitaxel, resolves within 7 days and affects mostly the large axial muscular and joint regions (15). Paclitaxel-induced acute pain following paclitaxel infusion has commonly been treated with nonsteroidal antiinflammatory drugs, acetaminophen and opioid pain medications (15). In addition, ShakuyakuKanzo-To (a Japanese herb) (11), corticosteroids (17), antihistamines (18), opioids (29) and amifostine (10) have been investigated for the prevention

Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it frequently causes peripheral neuropathy. Milnacipran, a serotonin/noradrenaline reuptake inhibitor and fluvoxamine, a selective serotonin reuptake inhibitor, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of paclitaxel-induced mechanical allodynia in mice by milnacipran and fluvoxamine. Paclitaxel was administered once per day (2 mg/kg, intraperitoneally (i.p.)) for 5 days to mice. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In paclitaxel-treated mice, mechanical allodynia was observed on days 3-15 of paclitaxel administration. A single administration of milnacipran (20 mg/kg, i.p.) or fluvoxamine (40 mg/kg, i.p.) had no effect on paclitaxel-induced mechanical allodynia. However, repeated administration of milnacipran (10, 20 mg/kg, once per day, i.p.) for 5 days significantly reduced paclitaxel-induced mechanical allodynia. In contrast, repeated fluvoxamine administration (40 mg/kg, once per day, i.p.) for 5 days resulted in a weak attenuation of paclitaxel-induced mechanical allodynia. These results suggest that chronic paclitaxel administration induces mechanical allodynia, and that repeated milnacipran administration may be an effective therapeutic approach for the treatment of neuropathic pain caused by paclitaxel treatment for cancer.Peripheral neurotoxicity induced by antineoplastic drugs (taxanes, vinca-alkaloids and platin-based compounds) is a clinically significant complication that can be dose-limiting and can substantially diminish quality of life. Paclitaxel is commonly used for the treatment of solid tumors and ovarian and breast cancers. Paclitaxel induces antimitotic actions by impeding the cell cycle in the late phases of mitosis, stabilizing microtubule formation, and ultimately inducing apoptosis (26). However, paclitaxelinduced peripheral neuropathy is a side-effect of chemotherapeutic treatment which often manifests as bilateral pain in the extremities in a stocking and glove-type distribution (6), sometimes greatly impairing the patients' quality of life and their ability to perform normal activities of daily living. To date, therapeutic drugs have been evaluated using various animal models of paclitaxel-induced allodynia. Ethosuximide (7), gabapentin (14), thalidomide and minocycline (3), neurotropin (11) and acetyl-L-carnitine (8) have been examined against the paclitaxelinduced neuropathic pain model, although studies regarding their efficacy have not been conclusive. Supplementary analgesics (antidepressants and anticonvulsants) have suppressive effects on opioid-resistant neuropathic pain (16,24), and antidepressants are widely used for the treatment of neuropathic pain. Antidepressants, especially tricyclic antidepressants (TCAs), are regarded as first-line drugs for the treatment of neuropathic pain (16). Recently, more selective monoamine reuptake inhibitors...