Neuroscience
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We have addressed the molecular mechanism(s) of hyperalgesia, which depends on increased excitability of dorsal horn neurons and on sensitization of primary afferent nociceptors, during peripheral inflammation. Following unilateral adjuvant-induced inflammation in the rat hind paw, time-course changes in behavioral hyperalgesia and functional activities of Ca2+/phospholipid-dependent protein kinase C isozymes were examined. Inflammation was characterized by increase in paw diameter, and behavioral hyperalgesia was quantified as paw withdrawal latency from a radiant heat source. ⋯ Quantitative immunohistochemical analyses demonstrated intensified protein kinase CbetaII-like immunoreactivity on the side of the spinal cord ipsilateral to the inflammation. Time-course for increases in the activity of membrane-associated protein kinase CbetaII, and in intensity of protein kinase CbetaII-immunoreactivity, paralleled inflammation-mediated changes in paw withdrawal latency and paw diameter. Our findings indicate an apparent involvement of protein kinase CbetaII isozyme specifically in the molecular mechanism(s) of thermal hyperalgesia.
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Heat transduction mechanisms in primary nociceptive afferents have been suggested to involve a vanilloid receptor channel with high calcium permeability. To characterize the changes in free cytosolic calcium evoked by noxious heat stimuli (< or =51 degrees C, 10s), we performed microfluorometric measurements in acutely dissociated small dorsal root ganglion neurons (< or =32.5 microm) of adult rats using the dye FURA-2. Only neurons that responded with a reversible increase in intracellular calcium to high potassium were evaluated. ⋯ Heat-induced calcium transients were also reversibly reduced by 75+/-6% in sodium-free solution and by 62+/-7% with the L-type calcium channel blocker nifedipine (5 microM). These results indicate that noxious heat rapidly increases intracellular calcium in nociceptive primary sensory neurons. Heat-sensitive vanilloid receptors are involved in the induction of calcium transients, and calcium is also released from intracellular stores, but the main fraction of calcium passes through voltage-operated calcium channels.
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Administration of cocaine to pregnant rabbits produces robust and long-lasting anatomical alterations in the dopamine-rich anterior cingulate cortex of offspring. These effects include increased length and decreased bundling of layer III and V pyramidal neuron dendrites, increases in parvalbumin expression in the dendrites of interneurons, and increases in detectable GABAergic neurons. We have now examined multiple cortical regions with varying degrees of catecholaminergic innervation to investigate regional variations in the ability of prenatal cocaine exposure to elicit these permanent changes. ⋯ These regions included the medial prefrontal, entorhinal, and piriform cortices. In contrast, primary somatosensory, auditory and motor cortices exhibited little tyrosine hydroxylase staining and no measurable cocaine-induced changes in cortical structure. From these data we suggest that the presence of dopaminergic afferents contributes to the marked specificity of the altered development of excitatory pyramidal neurons and inhibitory interneurons induced by low dose i.v. administration of cocaine in utero.
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Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. ⋯ Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.
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Loss of cholinergic neurons is found in the medial septum and nucleus basalis of Meynert in Alzheimer's disease. Recent observations suggest that cholinergic neurons down-regulate their phenotype and that growth factors may rescue cholinergic neurons. The aim of this study was to investigate whether cholinergic neurons of the basal nucleus of Meynert can be cultured in rat organotypic slices, and if nerve growth factor and glial cell line-derived neurotrophic factor can rescue the cholinergic phenotype. ⋯ In cultures incubated for up to nine weeks, it was also found that glial cell line-derived neurotrophic factor was capable of restoring the cholinergic phenotype. The low-affinity p75 and high-affinity trkA receptors, as well as the glial cell line-derived neurotrophic factor receptor GFRalpha-1, could be visualized in slices using immunohistochemistry. In conclusion, it is shown that, in the axotomized organotypic slice model, the number of cholinergic neurons is decreased, but can be partly restored by nerve growth factor and glial cell line-derived neurotrophic factor.