Paroxetine inhibited the relaxations induced by EFS in mice corpus cavernosum: is it a NOS inhibition?

Selective serotonin reuptake inhibitors are used in the treatment of psychiatric disorders but are associated with high incidence of sexual dysfunction such as ejaculation disorders by sertraline and fluoxetine, erection disorders by paroxetine. The aim of this study is to evaluate the effects of paroxetine, sertraline and fluoxetine on relaxation of smooth muscle of corpus cavernosum on the basis of nitric oxide (NO). Male mice were killed by cervical dislocation and their penile tissues were immediately removed. The tissues were incubated in organ baths containing Krebs solution at 37 degrees C and bubbled with 95% O(2) and 5% CO(2). The corpus cavernosum strips were contracted with 10(-5 )m phenylephrine (PHE) and relaxed with either paroxetine, sertraline, fluoxetine (10(-8)-10(-4 )m) or electrical field stimulation (EFS). The effects of paroxetine, sertraline and fluoxetine were examined on EFS-induced relaxations. While paroxetine did not show any effect on the corpus cavernosum strips precontracted with PHE, sertraline and fluoxetine caused a relaxation at concentrations of 3 x 10(-5)-10(-4 )m. The relaxations induced by sertraline and fluoxetine were completely abolished by L-NAME, but not D-NAME. The relaxations induced by EFS could be inhibited by L-NAME but not D-NAME. Paroxetine inhibited the relaxations at high concentrations. L-arginine potentiated the relaxations induced by EFS; however in the presence of paroxetine these relaxations were not observed. In contrast, sertraline (10(-8)-10(-5 )m) and fluoxetine (10(-8)-10(-5)m) increased the relaxations induced by EFS. Sertraline and fluoxetine seem to be releasing some relaxing factor(s) and this factor may be NO. Paroxetine probably has a NOS inhibitory activity either on nNOS or eNOS, in contrast to sertraline and fluoxetine.

Effects of dual inhibitor of cyclooxygenase and 5-lipoxygenase on acute necrotizing pancreatitis in rats.

BACKGROUND/AIMS: The aim of this study was to investigate the influence of dual inhibitor of cyclooxygenase and 5-lipoxygenase (ER-34122) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. METHODOLOGY: ANP was induced in 96 rats by standardized intraductal glycodeoxycholic acid infusion and intravenous cerulein infusion. Rats were divided into six groups (6 rats in each group): Sham + saline, sham + ER-34122, which was dissolved in hydroxypropylmetylcellulose (TC-5RW), sham + TC-5RW, ANP + saline, ANP + ER-34122 and ANP + TC-5RW. Six hours after ANP induction ER-34122 (30 mg/kg), saline or TC-5RW was given by feeding tube. At the 12th hour, routine cardio-respirator, renal parameters were monitored to assess organ function. Serum amylase, alanine amino transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lung were measured. Pancreas histology was examined. In the second part of the study 60 rats were studied in four groups similar to first part. Survival of all rats was monitored for 24 hours. RESULTS: The induction of ANP resulted in significant increase in mortality rate, pancreatic necrosis and serum activity of amylase, ALT, IL-6, LDH in BAL fluid, serum concentration of urea, tissue activity of MPO and MDA in pancreas and lung, and significant decrease of serum concentrations of calcium, blood pressure, urine output and pO2. NAC did not change serum activity of amylase. The use of ER-34122 inhibited the changes in blood pressure, pO2, serum activity of ALT, pancreatic MPO and MDA levels, partially urine output, LDH level in BAL fluid and pancreatic damage. But ER-34122 could not effect the changes, such as serum activity of amylase, IL-6, serum concentration of urea and calcium, MPO and MDA levels in lung and the mortality rate. CONCLUSIONS: The use of ER-34122 has a limited value on the course of ANP. It has no role in the treatment of ANP.

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.

Effects of the celecoxib on the acute necrotizing pancreatitis in rats.

The investigation of the effects of the celecoxib as a cylooxygenase-2 (COX-2) inhibitor on the course of the acute necrotising pancreatitis (ANP) in rats. ANP was induced in 72 rats by standardized intraductal glycodeoxycholic acid infusion and intravenous cerulein infusion. The rats were divided into four groups (six rats in each group): Sham + saline, sham + celecoxib, ANP + saline, ANP + celecoxib. Six hours later after the ANP induction, celecoxib (10 mg/kg) or saline was given i.p. In the 12th hour, routine cardiorespiratuar, renal parameters were monitored to assess the organ function. The serum amylase, alanine amino transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, the serum concentration of the urea, the tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lungs were measured. The pancreas histology was examined. In the second part of the study, 48 rats were studied in four groups similar to the first part. Survival of all the rats after the induction of ANP was observed for 24 h. The induction of the pancreatitis increased the mortality from 0/12, in the sham groups to 4/12 (30%) in the acute pancreatitis with saline group, 5/12 (42%) in the acute pancreatitis with celecoxib group respectively, heart rate, the serum activities of amylase, ALT, the tissue activities of MPO, MDA in the pancreas and lung, and LDH in BAL fluid, the serum concentration of the urea and IL-6, the degree of the pancreatic damage and decreased the blood pressure, the urine production, pO(2) and the serum concentration of calcium. The use of celecoxib did not alter these changes except the serum IL-6 concentration, urine production and MPO, MDA activities in the tissue of the lungs and pancreas. Serum urea concentration and pancreatic damage in ANP + celecoxib group were insignificantly lesser than ANP + saline group. Whereas treatment with celecoxib improves lung and renal functions, the degree of pancreatic damage partially and the serum IL-6 level completely, it does not improve the cardiovascular and liver functions, the mortality rate and the calcium level. Celecoxib may be useful for the support of some organ functions during ANP in rats.