Neuropharmacology
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Comparative Study
Comparative antiallodynic activity of morphine, pregabalin and lidocaine in a rat model of neuropathic pain produced by one oxaliplatin injection.
A single infusion of oxaliplatin, a drug active against colorectal cancer, induces specific painful syndrome characterized by neurosensitive symptoms triggered or aggravated in cold conditions. In an animal model that reproduces such hypersensitivity to cold for five days after a single oxaliplatin administration (6mg/kg, i.p.), we assessed the antinociceptive efficacy of intravenously administered drugs such as morphine, lidocaine and pregabalin using the rat tail immersion test in cold water (10 degrees C). The antinociceptive efficacy was first ranked by ratio of the pharmacological effect (versus time) to dose: pregabalin (2mg/kg)>lidocaine (3mg/kg)>morphine (4mg/kg). Our results show that pregabalin may be a good choice to treat cold hypersensitivity after one oxaliplatin injection.
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Interneuronal networks in the spinal ventral horn are plausible substrates for mediating anesthetic-induced immobility. Here, we investigated how their activity is affected by clinically relevant concentrations of thiopental, a barbiturate in clinical use. In cultured spinal cord slices from mice, thiopental reduced action potential activity with an EC(50) of 16.6+/-2.4microM. ⋯ Furthermore, at this concentration, activity-depressing mechanisms independent of GABA(A) receptors came into play. The results suggest that in the spinal ventral horn thiopental acts mostly, but not exclusively, via GABA(A) receptors. With increasing concentrations of the drug, inhibition via sIPSCs is limited by negative feedback on interneuronal firing whereas action potential-independent GABAergic inhibition due to tonic currents gains progressively in impact.
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The present work investigated sites of ethanol action in ATP-gated P2X receptors (P2XRs) using chimeric strategies that exploited the differences in ethanol response between P2X2R (inhibition) and P2X3R (potentiation). We tested ethanol (10-200mM) effects on ATP- and alpha,beta-methylene-ATP (alpha,beta-meATP)-induced currents in wildtype P2X2, P2X3 and chimeric P2X2/P2X3Rs expressed in Xenopus oocytes using two-electrode voltage-clamp (-70mV). Exchanging ectodomain regions of P2X2 and P2X3Rs reversed wildtype ethanol responses. ⋯ Studies that substituted TM regions of P2X3R with respective P2X2R TMs indicate that the TM1, but not the TM2, region plays a role in determining the magnitude of ethanol response. Studies with ATP and alpha,beta-meATP support prior indications that TM regions are important in agonist desensitization and suggest that both ectodomain and TM regions play roles in determining agonist potency and selectivity. Overall, these findings are the first to identify potential targets for ethanol in P2X2 and P2X3Rs and should provide insight into the sites of ethanol action in other P2XRs.
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T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate) is a candidate therapeutic agent for Alzheimer's disease that inhibits oxidative stress and nitric oxide-induced neurotoxicity and acts as a neurotrophic factor. The present study examines the effect of T-817MA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6J mice. MPTP treatment (10mg/kg, s.c.x4 at 2-h intervals) impaired rotarod performance, and T-817MA improved this deficit. ⋯ MPTP increased levels of the lipid peroxidation product, thiobarbituric acid reactive substance, only in the midbrain, which could be blocked by T-817MA. MPTP caused microglial activation both in the SNc and striatum, but T-817MA did not affect the activation of microglia. These results suggest that T-817MA protects against MPTP-induced neurotoxicity by blocking lipid peroxidation in the SNc, and imply that this compound may be useful for treating neurodegenerative disorders related to oxidative stress, such as Parkinson's disease.
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The neurobiological mechanisms governing alcohol-induced alterations in anxiety-like behaviors are not fully understood. Given that the amygdala is a major emotional center in the brain and regulates the expression of both learned fear and anxiety, neurotransmitter systems within the basolateral amygdala represent likely mechanisms governing the anxiety-related effects of acute ethanol exposure. It is well established that, within the glutamatergic system, N-methyl-d-aspartate (NMDA)-type receptors are particularly sensitive to intoxicating concentrations of ethanol. ⋯ Lastly, to better understand the relationship between KA-R activity and anxiety-like behavior, we bilaterally microinjected ATPA directly into the BLA. We observed an increase in measures of anxiety-like behavior, assessed in the light/dark box, with no change in locomotor activity. This evidence suggests that kainate receptors in the BLA are inhibited by pharmacologically relevant concentrations of ethanol and may contribute to some of the acute anxiolytic effects of this drug.