Analgesic effects of antidepressants alone and after their local co-administration with morphine in a rat model of neuropathic pain.

BACKGROUND: The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies. METHODS: This study was performed on rats after chronic constriction injury (CCI) to the sciatic nerve. The von Frey and Hargreaves' tests were used to assess mechanical allodynia and thermal hyperalgesia, respectively, after intraplantar (ipl) or subcutaneous (sc) administration of amitriptyline, doxepin, or venlafaxine, or their ipl co-administration with morphine on day 12-16 after injury. RESULTS: The ipl administration of amitriptyline (3, 15 mg), doxepin (1, 5, 10, 15 mg), or venlafaxine (2, 7 mg) was effective in antagonizing CCI-induced allodynia. Their sc injection at a site distal to the injured side, did not induce alterations in pain thresholds, which supports the local mode of action. Of the three antidepressants used in this study, only ipl co-administration of amitriptyline with morphine significantly enhanced its effect in contrast to doxepin and venlafaxine, both of which weakened the analgesic effect of morphine. CONCLUSIONS: In summary, the results suggest that when amitriptyline (but not doxepin or venlafaxine) is locally co-administered with morphine the effectiveness under neuropathic pain is enhanced, although additional studies are necessary to explain differential mechanisms of interaction of antidepressant drugs with morphine after local administration.

Effects of new antiepileptic drugs and progabide on the mitogen-induced proliferative activity of mouse splenocytes.

Classical antiepileptic drugs are known to affect immune system activity, although the effects of new generation anticonvulsants on T- and B-cell-mediated immunity remain unknown. Therefore, in the present study, we compared a selection of new antiepileptic drugs with classical ones in terms of their effects on the proliferative activity of lymphocytes stimulated by concanavalin A(Con A) and lipopolysaccharide (LPS). Felbamate (3 x 10(-6) - 10(-4) M) was the most potent in inhibiting [(3)H]-thymidine incorporation in C57BL/6 mouse spleen cells stimulated by Con A and LPS. Treatment of the cells with stiripentol (3 x 10(-5) and 10(-4) M) and loreclezole (10(-4) M) suppressed the proliferative activity of splenocytes both after Con A and LPS stimulation. Tiagabine (3 x 10(-5) M and 10(-4) M) inhibited the Con A-induced cell proliferation, whereas the effect of LPS was attenuated only by the highest concentration of this drug (10(-4) M). Progabide showed immunosuppressive effects at concentrations of 3 x 10(-5) and 10(-4) M or only 10(-4) M after LPS or Con A stimulation, respectively. No effect on the immune parameters was observed after lamotrigine treatment. On the other hand, the Con A-induced proliferation of splenocytes was enhanced by carbamazepine (10(-5) - 10(-4) M) and sodium valproate (5 x 10(-4) - 3 x 10(-3) M). Neither carbamazepine nor sodium valproate affected the LPS-induced proliferation. These data indicate that some new antiepileptic drugs, especially felbamate at pharmacological concentrations, may suppress the mitogen-stimulated proliferative activity of mouse splenocytes. In contrast, two classical anticonvulsants (carbamazepine and sodium valproate) stimulated T-cell-mediated immunity. The above differences in the effects of particular antiepileptic drugs on the immune response may play roles in both their therapeutic efficiency and undesired effects.

[Origin of abdominal herniae--anatomical aspects]. / Anatomiczne aspekty powstawania przepuklin brzusznych.

Based on anatomical background authors review the current knowledge on mechanisms and anatomical predisposes causing abdominal herniations. They are giving a brief summary of limitations of potential spaces involved into dislocation of abdominal visceral through natural spaces. Authors try to join anatomical knowledge with clinical information what might be useful in understanding of the patomechanism of these surgical disorders.

Effects of some new antiepileptic drugs and progabide on glucocorticoid receptor-mediated gene transcription in LMCAT cells.

Antiepileptic drugs affect endocrine and immune system activity, however, it is not clear whether these effects are indirect, via interference with neurotransmitters, membrane receptors and ion channels or maybe independent of neuronal mechanisms. In order to shed more light on this problem, in the present study, we evaluated effects of some new-generation antiepileptic drugs and progabide as a GABA-mimetic on the corticosterone-induced chloramphenicol acetyltransferase (CAT) activity in mouse fibroblast cells stably transfected with mouse mammary tumor virus (MMTV)-CAT plasmid. Treatment of cells with felbamate for five days inhibited in a concentration-dependent manner (3-100 microM) the corticosterone-induced reporter gene transcription. Progabide and loreclezole also inhibited the corticosterone-induced CAT activity, but with lower potency, and significant effects were observed at 10 to 100 microM concentration. Tiagabine and stiripentol showed less potent inhibitory effect on functional activity of glucocorticoid receptors (GR). In contrast, topiramate and lamotrigine (3-100 microM) failed to affect the corticosterone-induced gene transcription. These data indicate that some new antiepileptic drugs and progabide may suppress glucocorticoid effects via the inhibition of GR-mediated gene transcription. In turn, attenuation of GR function could influence antiepileptic drug effect on seizures, neuronal degeneration and immune system activity.

Effect of acute and repeated treatment with mirtazapine on the immunity of noradrenaline transporter knockout C57BL/6J mice.

Pathological immunoactivation is thought to play an important role in the etiology of depression; however, the effect of novel antidepressant drugs on immunity has been poorly recognized. Mirtazapine, an antidepressant drug, enhances noradrenergic and serotonergic neurotransmissions, which are crucially involved in the regulation of immune system activity. In the present study we examined the effect of acute and seven-day repeated administration of mirtazapine (20 mg/kg, i.p.) on immunoreactivity in noradrenaline transporter knockout (NET-KO) and wild-type male C57BL/6J mice subjected to the forced swimming test (FST). Mirtazapine decreased immobility time in the FST after acute, but not seven-day repeated, administration to C57BL/6J mice. Lack of the antidepressant effect of mirtazapine was observed, after acute and repeated administration to NET-KO mice, although those mice showed a significantly shorter immobility time in the FST than did wild-type animals. Seven-day repeated mirtazapine administration to wild-type mice suppressed the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines, whereas production of IL-4 was stimulated. Acute mirtazapine administration did not change immune parameters in C57BL/6J mice. In NET-KO mice, acute and seven-day repeated mirtazapine administration reduced the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines. This study indicates that, in comparison with wild-type C57BL/6J mice, NET-KO mice show enhanced mobility, which is not further potentiated by mirtazapine treatment. Furthermore, the NET-KO mice display higher susceptibility to the immunosuppressive effects of mirtazapine than do the wild-type animals. The present paper postulates an essential role of noradrenergic system in the immunological and behavioral effects of mirtazapine.

Effects of some new antidepressant drugs on the glucocorticoid receptor-mediated gene transcription in fibroblast cells.

Antidepressant drugs are thought to counteract effects of hypercortisolemia, frequently associated with depression, by lowering cortisol level and by modifying the function of glucocorticoid receptors (GR). Indeed, classical antidepressants inhibit corticosteroid-induced gene transcription in cell cultures. The aim of the present study was to investigate effects of new generation antidepressant drugs on GR function in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). It has been found that reboxetine (at 10 and 30 microM), venlafaxine, citalopram and mirtazapine (at 30 microM), but not milnacipran, in statistically significant manner inhibited corticosterone-induced gene transcription. However, the effects of new generation antidepressant drugs were weaker than those evoked by imipramine, which was active already at 3 microM concentration. Further studies on the mechanism of antidepressant action on GR function revealed that protein kinase C, but not mitogen-activated protein kinases (MAPK), glycogen synthase kinase (GSK-3) and protein kinase B (PKB, Akt) play a role in this phenomenon.