The involvement of opioid receptor activation in the antinociceptive effect of either fluvoxamine, a selective serotonin reuptake inhibitor, or serotonin (5-HT) on thermal hyperalgesia and mechanical allodynia in a model of neuropathic pain in mice induced by sciatic nerve ligation was examined. The experiments were conducted 2 or 6 weeks after unilateral sciatic nerve ligation. Ipsilateral thermal hyperalgesia and mechanical allodynia were observed both 2 and 6 weeks after sciatic nerve ligation. Neither s.c. fluvoxamine nor i.t. 5-HT affected sciatic nerve ligation-induced thermal hyperalgesia or mechanical allodynia in mice 2 weeks after sciatic nerve ligation. However, the same dose of either fluvoxamine or 5-HT significantly reduced mechanical allodynia but not thermal hyperalgesia in sciatic nerve ligated mice 6 weeks after surgery. The antinociceptive effect of fluvoxamine on sciatic nerve ligation-induced mechanical allodynia in mice 6 weeks after surgery was completely abolished by pretreatment with either naloxone, a nonselective opioid receptor antagonist, or β-funaltrexamine, a selective μ-opioid receptor antagonist. Furthermore, pretreatment with naltrindole, a selective δ-opioid receptor antagonist, partially but significantly inhibited the antinociceptive effect of fluvoxamine in sciatic nerve ligated mice at the 6th postoperative week. The antinociceptive effect induced by i.t. 5-HT was also completely antagonized by either naloxone or β-funaltrexamine, and partially inhibited by naltrindole. However, pretreatment with nor-binaltorphimine, a selective κ-opioid receptor antagonist, had no effect against either s.c. fluvoxamine- or i.t. 5-HT-induced antinociception. These results suggest that the antinociceptive effect of s.c. fluvoxamine or i.t. 5-HT in the chronic state of sciatic nerve ligation-induced neuropathic pain may be related to opioidergic activity, mainly through the activation of spinal μ- and δ-opioid receptors.
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