Antinociceptive effects of fluoxetine and paroxetine with their related actions on glycemia in mice.

OBJECTIVES: Clinical and experimental trials have demonstrated that some of selective serotonin reuptake inhibitors (SSRIs) have some suspicious effects on blood glucose levels in different directions. Especially fluoxetine and sertraline are studied in this point of view. These drugs are also used in treatment of depression and peripheral neuropathy in diabetic patients. Paroxetine and fluoxetine, members of this drug group, besides having antidepressant effects were shown to have antinociceptive effects in animals and humans. They can be used in the treatment of chronic pain as an adjuvant drug or alone. But less is known about their actions on pain in case of diabetes. The aim of this study is to investigate the antinociceptive effects of fluoxetine and paroxetine in diabetic and non-diabetic mice while monitoring their effects on blood glucose levels. METHODS: Mice of either sex were randomly used in experiments. The antinociceptive effects of paroxetine and fluoxetine were evaluated using hot plate test both in diabetic and non-diabetic mice. The effects of these drugs on blood glucose levels were also evaluated in another group of mice both in diabetic and non-diabetic mice. RESULTS: Fluoxetine and paroxetine showed significant antinociceptive effect at all doses and at all times tested in non-diabetic mice, but they could not successfully show this effect in diabetic mice. They also had controversial effects on blood glucose levels. CONCLUSION: Although they showed increasing or decreasing effects on blood glucose levels in non-diabetic and diabetic mice, they showed antinociception on hot-plate test showing dissociation between blood glucose levels and analgesia.

Effect of gender on antinociceptive effect of paroxetine in hot plate test in mice.

PURPOSE: Many studies have reported both a gender difference in the rates of depression and its treatment by using any of the widely used antidepressant drug groups. Some studies suggest that females respond more poorly to tricyclic antidepressants than males and appear to respond better to selective serotonin reuptake inhibitors (SSRI). There is no study investigating the analgesic/antinociceptive effects of antidepressant drugs on the basis of gender difference. In this study, we aimed to investigate the antinociceptive effect of paroxetine on the basis of gender difference. METHODS: The antinociceptive effect of paroxetine was tested using hot plate test in Balb/c mice (30-40 g). The animals were divided into eight groups on the basis of gender. FINDINGS: While paroxetine did not induce an antinociceptive effect in both sex at a dose of 1 mg kg(-1), it showed significant antinociceptive effects in both sex at a dose of 5 or 10 mg kg(-1). None of the doses of paroxetine revealed a gender difference in its antinociceptive action. CONCLUSION: There are several studies showing positive or negative evidence on the gender difference of paroxetine's antidepressant effect, but in the literature there is no study about the gender difference of paroxetine's or any other SSRI drug's antinociceptive effect. In conclusion, our results do not show any gender difference in antinociceptive effect of paroxetine that may be important especially when it would be used as an adjuvant agent in some painful conditions.

The different roles of 5-HT(2) and 5-HT(3) receptors on antinociceptive effect of paroxetine in chemical stimuli in mice.

Serotonin (5-HT) is known to be an important mediator in pain modulation. Some centrally acting agents, like selective serotonin reuptake inhibitors (SSRIs), modulate pain. Activation of the endogenous opioid mechanisms or potentiation of analgesic effect by serotonergic and/or noradrenergic pathways might be involved in antinociception of SSRIs. However, peripheral mechanisms of nociception are not clear. In this study, the antinociceptive effect of paroxetine, its interaction with the opioidergic system and serotonin receptors were tested using the writhing test in mice. Paroxetine (5, 10, 20 mg/kg) induced an antinociceptive effect following i.p. administration in writhing test. For the groups in which the antagonists were tested, the dose of paroxetine that caused a significant and equipotent analgesic effect similar to 0.5 mg/kg morphine was selected. Naloxone significantly antagonized the antinociceptive effects of both paroxetine and morphine in a similar pattern and magnitude. Ketanserin (5-HT(2)-receptor antagonist) or ondansetron (5-HT(3)-receptor antagonist) alone did not alter the nociceptive action of acetic acid. While the antinociceptive effect of paroxetine was highly potentiated by ketanserin, ondansetron reduced that antinociception. In conclusion, our results indicate that the antinociceptive effect of paroxetine mainly depends on central opioidergic and serotonergic mechanisms. Peripheral serotonergic mechanisms/receptors may contribute to this antinociceptive effect, especially by 5-HT(3)-receptor subtypes.

Possible involvement of opioidergic and serotonergic mechanisms in antinociceptive effect of paroxetine in acute pain.

Antidepressant drugs, especially tricyclics have been widely used in the treatment of chronic pain, but not in acute pain. Because of numerous undesirable side effects, the selective serotonin reuptake inhibitors (SSRIs), with their favorable side effect profile, are preferred nowadays. An activation of the endogenous opioid mechanisms or potentiation of the analgesic effect mediated by serotonergic and/or noradrenergic pathways are thought to be involved in the antinociceptive action of SSRIs. In this study, the potential antinociceptive effect of paroxetine and its interaction with opioidergic system and serotonin receptors were evaluated. The antinociceptive effect of paroxetine was tested using a hot plate test in mice. Paroxetine, a SSRI antidepressant drug, induced an antinociceptive effect following i.p. administration. This antinociception was significantly inhibited by naloxone, an opioid receptor antagonist, suggesting the involvement of opioidergic mechanisms. While ondansetron (a 5-HT(3)-receptor antagonist) inhibited the effect of paroxetine, ketanserin (a 5-HT(2)-receptor antagonist) could not. In conclusion, paroxetine-induced antinociception, similar to morphine, suggests an involvement of direct or indirect action (via an increase in release of endogenous opioid peptide(s)) at opioid receptor sites and an involvement of serotonergic mechanisms mainly at the receptor level.