Neuropharmacology
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Etomidate and propofol have clearly distinguishable effects on the central nervous system. However, studies in knock-in mice provided evidence that these agents produce anesthesia via largely overlapping molecular targets, namely GABA(A) receptors containing beta3 subunits. Here the authors address the question as to whether etomidate and propofol are targeting different subpopulations of beta3 subunit containing GABA(A) receptors. ⋯ Etomidate and propofol alter the firing patterns and GABA(A) receptor-mediated inhibition of neocortical neurons in different ways. This suggests that etomidate and propofol act via non-uniform molecular targets. Because the major effects induced by these anesthetics were attenuated by the beta3(N265M) mutation, different subpopulations of beta3-containing GABA(A) receptors are likely to be involved.
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Chronic morphine treatment and persistent pain stimuli trigger translocation of delta-opioid receptors (DORs) from cytosolic pools to the surface membrane. Previously, we reported that chronic treatment with morphine induces functional DORs on GABAergic nerve terminals impinging on some neurons in the midbrain periaqueductal grey. In the present investigation, we used chronic administration of morphine in adult rats to study delta and mu-opioid receptors in the central nucleus of amygdala (CeA), a brain region with a substantial (presumed) GABAergic projection to the periaqueductal grey. ⋯ Other physiological properties of amygdala neurons did not differ between neurons from vehicle and morphine-treated animals. Taken together, these results indicate that chronic treatment with morphine upregulates functional DORs in neurons projecting from the CeA to periaqueductal grey. CeA-periaqueductal grey projections form part of the descending antinociceptive and autonomic control systems suggesting an upregulation of functional DOR in antinociception, emotion and anxiety following chronic morphine treatment.
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Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. Reactive oxygen/nitrogen species, cytokines and apoptosis are implicated in the pathogenesis of diabetic neuropathy. ⋯ Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced beneficial effect as compared to their per se groups. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, combination with tocotrienol not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release and caspase-3 in the diabetic rats and thus it may find clinical application to treat neuropathic pain in the diabetic patients.
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Diabetic neuropathic pain remains an unmet clinical problem and is poorly relieved by conventional analgesics. N-methyl-D-aspartate (NMDA) receptors play an important role in central sensitization in neuropathic pain. Although NMDA antagonists are highly effective in reducing neuropathic pain, these agents cause severe side effects at therapeutic doses, which limit their clinical uses. ⋯ The plasma level achieved by neramexane at 12.3, 24.6, and 49.2 mg/kg/day was 0.26 +/- 0.04, 0.50 +/- 0.05, and 1.21 +/- 0.16 microM, respectively. These data suggest that neramexane at therapeutically relevant doses attenuates diabetic neuropathic pain. Our study provides valuable information about the therapeutic potential of chronic administration of neramexane and memantine for painful diabetic neuropathy.
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Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was suggested to possess anxiolytic actions 30 years ago. Hoffmann-La Roche researchers recently reported that it is a selective and potent mGlu5 receptor antagonist, acting as a negative allosteric modulator. In the present study, we show that fenobam readily penetrates to the brain, reaching concentrations over 600 nM, clearly above the affinity for mGluR5 receptors. ⋯ Fenobam also impaired performance in both the Morris water maze and in the contextual fear conditioning test at the doses of 30 and 10 mg/kg, respectively. Prepulse inhibition, used as a model of psychomimetic activity, was not affected by fenobam at doses of up to 60 mg/kg. Our results indicate that the beneficial effects of fenobam occur in a similar dose range as the potential side-effects.