Neuroscience
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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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Voltage-dependent Na-currents were studied, using whole cell voltage clamp, in acutely dissociated, large (mostly Abeta-fiber type) cutaneous afferent dorsal root ganglia neurons (L(4) and L(5)) from the adult rat. Cells were dissociated 14-17 days after axotomy. Control and axotomized neurons were identified via the retrograde marker hydroxy-stilbamide (fluorogold) which was injected into the lateral and plantar region of the skin of the foot and were studied using whole cell patch clamp techniques within 12-20 h of dissociation and plating. ⋯ However, while 77% of control large neurons were observed to express the slower inactivating, tetrodotoxin-resistant current, only 45% of these large neurons did after axotomy. These results indicate that large adult cutaneous afferent dorsal root ganglion neurons (Abeta-type) express tetrodotoxin-sensitive Na-currents, which have much faster repriming than Na-currents in small (C-type) neurons, both before, and after axotomy. Like small neurons, the majority of large neurons downregulate the tetrodotoxin-resistant current following sciatic nerve section.
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Hippocampal cholinergic neurostimulating peptide, an undecapeptide originally isolated from the hippocampus of young rats, enhances acetylcholine synthesis in rat medial septal nucleus in vitro. Hippocampal cholinergic neurostimulating peptide is derived from the N-terminal region of its 21-kmol.wt precursor protein. ⋯ Selective inhibition with pharmacological agents revealed that the constitutive hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA level can be up-regulated by D-(-)-2-amino-5-phosphono-valeric acid, and that activity-dependent transcription can be inhibited by tetrodotoxin, nifedipine, 6-cyano-7-nitroquinoxaline-2,3-dione, and scopolamine, but not by mecamylamine. These results indicate that septal cholinergic neurons and hippocampal glutamatergic neurons exert a reciprocal influence over the expression of hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA in the hippocampus, and that the activity-dependent and constitutive expressions of hippocampal cholinergic neurostimulating peptide precursor protein messenger RNA may be regulated by different routes, involving calcium influx via L-type Ca(2+) channels and N-methyl-D-aspartate receptors.
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We examined the effects of the neuropeptide nociceptin/orphanin FQ on activity of the limbic-hypothalamic-pituitary-adrenal axis (also known as the stress axis) in rats. This axis regulates important metabolic functions, and initiates critical neuroendocrine responses that cope with environmental threats and challenges to homeostatic functioning. Disregulation of the limbic-hypothalamic-pituitary-adrenal axis is associated with impaired physical and psychological health. ⋯ We conclude that administration of nociceptin/orphanin FQ activates neuroendocrine activity of the limbic-hypothalamic-pituitary-adrenal axis even in the absence of a stressor, and may delay the shutdown of these physiological responses after exposure to acute mild stress. In light of the known functions of this axis, it appears that nociceptin/orphanin FQ participates in the regulation of important metabolic functions, and may be implicated in physiological responses to stress. This interaction between nociceptin/orphanin FQ and the limbic-hypothalamic-pituitary-adrenal axis implicates nociceptin/orphanin FQ in important aspects of physiological and psychological well-being.
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Huperzine A, a nootropic alkaloid isolated from a Chinese herb, has been proposed as one of the most promising agents to treat Alzheimer's disease. Recently, the agent was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in rat cerebral cortex in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the mechanisms underlying NMDA receptor inhibition were investigated using whole-cell voltage-clamp recording in CA1 pyramidal neurons acutely dissociated from rat hippocampus. ⋯ However, addition of spermine (200 microM) to the external solution caused a parallel shift to the right of the huperzine A concentration-response curve. From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites. The potential relevance of NMDA receptor antagonist activity of huperzine A to the treatment of Alzheimer's disease is discussed.