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 formalin-induced 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.
Exosomes are small (40-150 nm) membrane vesicles of endocytic origin that are found in many bodying fluids including blood and urine, and supporting their role in intercellular communication. Although recent studies have demonstrated that various biomarkers involved in the extent of pain from the serum exosomes, the effects of exosomes on the onset and progress of pain have not been elucidated. The objective of this study was to identify the relationship between serum exosomes in mice with partial sciatic nerve ligation (PSL) and alterations of nociceptive responses induced by 0.5% formalin.
Vincristine is an anticancer drug used to treat a variety of cancer types, but it frequently causes peripheral neuropathy. Neuropathic pain is often associated with the appearance of abnormal sensory signs, such as allodynia. Milnacipran and duloxetine, serotonin/noradrenaline reuptake inhibitors, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of vincristine-induced mechanical allodynia in mice by milnacipran and duloxetine. To induce peripheral neuropathy, vincristine was administered once per day (0.1 mg/kg, intraperitoneally (i.p.)) for 7 days. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In vincristine-treated mice, mechanical allodynia was observed on days 3–28 of vincristine administration. A single administration of milnacipran (40 mg/kg, i.p.) or duloxetine (20 mg/kg, i.p.) had no effect on vincristine-induced mechanical allodynia. However, repeated administration of milnacipran (20 or 40 mg/kg, once per day, i.p.) or duloxetine (5, 10, or 20 mg/kg, once per day, i.p.) for 7 days significantly reduced vincristine-induced mechanical allodynia. These results suggest that chronic vincristine administration induces mechanical allodynia, and that repeated milnacipran and duloxetine administration may be an effective approach for the treatment of neuropathic pain caused by vincristine treatment for cancer.
Morphine with its potent analgesic property has been widely used for the treatment of various kinds of acute pain and for long-term treatment of severe chronic pain. However, the chronic use of morphine is complicated by unwanted side-effect, including a paradoxical increase in pain sensitivity (i.e. hyperalgesia and allodynia). Indeed, continuous morphine infusion by osmotic pump caused allodynia in mice. The morphine-induced allodynia was inhibited by an antisera against dynorphin. However, the selective k-opioid receptor antagonist, nor-BNI did not prevent the morphine-induced allodynia. Dynorphin is rapidly degrated by a dynorphin-converting enzyme (cystein protease), to leucine-enkephalin (Leu-ENK). The morphine-induced allodynia was inhibited by an antisera against Leu-ENK. We also showed that the morphine co-administrated with Leu-ENK-converting enzyme inhibitors, phosphoramidon and bestatin produced much stronger behavioral responses than morphine alone. Furthermore, the morphine-induced allodynia was inhibited by intrathecal injection of the non-selective delta-opioid receptor antagonist, naltrindole or selective delta-2 opioid receptor antagonist, naltriben, while the selective delta-1 opioid receptor antagonist, BNTX had no effect. Taken together, these results suggest that continuous morphine infusion-induced allodynia may be triggered through the delta-2 opioid receptors activated by Leu-ENK which is formed from dynorphin in the spinal cord.
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