European journal of pharmacology
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Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. ⋯ In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.
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Acute cholestasis is associated with increased activity of the endogenous opioid system that results to changes including analgesia. N-methyl-d-aspartate (NMDA) receptors are involved in the nociceptive pathway and play a major role in the development of morphine induced analgesia. The magnesium acts as a non-competitive NMDA receptor antagonist by blocking the NMDA receptor channel. ⋯ In acute treatment, MK-801 (0.1 mg/kg, b.i.d), but not magnesium (150 mg/kg magnesium sulfate, i.e. 30 mg/kg of Mg(+2), i.p., b.i.d.) increased antinociception in cholestatic rats compared to saline treated cholestatics (P<0.05). In chronic treatment, administration of MK-801 or magnesium sulfate for 7 consecutive days, increased tail-flick latency (P<0.05, P<0.01) in cholestatic animals compared to saline treated cholestatics. These data showed that NMDA receptor pathway is involved in modulation of cholestasis-induced antinociception in rats and that repeated dosages of magnesium sulfate similar to MK-801 is able to modulate nociception in cholestasis.
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Pregabalin, ((S)-3-(aminomethyl)-5-methylhexanoic acid, also known as (S)-3-isobutyl GABA, Lyricatrade mark) is approved for treatment of certain types of peripheral neuropathic pain and as an adjunctive therapy for partial seizures of epilepsy both the EU and the USA and also for generalized anxiety disorder in the EU. Though pregabalin binds selectively to the alpha(2)-delta (alpha(2)-delta) auxiliary subunit of voltage-gated calcium channels, the cellular details of pregabalin action are unclear. The high density of alpha(2)-delta in skeletal muscle fibers raises the question of whether pregabalin alters excitation-contraction coupling. ⋯ Our data are consistent with pregabalin having no effect on striated muscle L-type calcium channel function. However, in mice expressing mutant (R217A) alpha(2)-delta Type 1, there was no significant effect of pregabalin on nerve-evoked muscle contraction. We propose that pregabalin reduces presynaptic neurotransmitter release without altering postsynaptic receptors or contraction coupling and that these effects require high affinity binding to alpha(2)-delta Type 1 auxiliary subunit of presynaptic voltage-gated calcium channels.
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This paper reviews the mechanisms of interaction of organophosphorus compounds with cholinesterases and clinical signs of acute poisoning. Further, we describe the current understanding of the mechanisms of action of pyridinium oximes pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6, Toxogonin), HI-6 and HLö-7 which are used as cholinesterase reactivators in the treatment of poisoning with organophosphorus compounds. We also review the most important literature data related to the efficacy of these oximes in the treatment of poisoning with warfare nerve agents soman, sarin, tabun, VX and cyclosarin and organophosphorus insecticides. Finally, we discuss the criteria for selection of oximes intended for further development as antidotes in poisoning with organophosphorus compounds and auto-injectors for their application in urgent situations.
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The effect of systemic administration of lacosamide, a newly developed anti-epileptic, on neuropathic pain-like behaviors was examined in rats after ischemic injury to the infraorbital nerve or spinal cord using a photochemical method. In rats with infraorbital nerve injury, lacosamide reduced mechanical hypersensitivity and the effect was markedly stronger in female than in male rats. In spinal cord injured female rats 10-20 mg/kg lacosamide dose-dependently alleviated the mechanical and cold allodynia-like behaviors without causing motor impairments or marked sedation. ⋯ Lacosamide also produced hypothermia at antinociceptive doses in rats. It is suggested that this novel compound may be useful as an analgesic for treating central and trigeminal neuropathic pain. Furthermore, there may be a gender difference to the effect of lacosamide with female rats being more responsive to the treatments.