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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While clinical characteristics of diabetic painful neuropathy are well described, the underlying electrophysiological basis of the exaggerated painful response to stimuli, as well as the presence of spontaneous pain, are poorly understood. In order to elucidate peripheral contributions to painful diabetic neuropathy, we quantitatively evaluated the function of C-fibers in a rat model of painful diabetic neuropathy, diabetes induced by the pancreatic beta-cell toxin streptozotocin. While there was no significant effect of diabetes on conduction velocity, mechanical threshold or spontaneous activity, the number of action potentials in response to sustained threshold and suprathreshold mechanical stimuli was significantly increased in the diabetic rats. ⋯ In summary, in an established model of painful diabetic neuropathy in the rat, a subset of C-fibers demonstrated a marked hyper-responsiveness to mechanical stimuli. The subset was also found to have a greater mean conduction velocity than the fibers not demonstrating this hyper-responsivity. The present findings suggest that study of individual neurons in vitro may allow elucidation of the ionic basis of enhanced nociception in diabetic neuropathy.
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Previous studies suggest that Fgf8 has a key role in regulating vertebrate development. In the rostral head of the embryonic chicken, there are increasing numbers of separate Fgf8 domains; these are present in tissues that appear to have previously expressed Otx2. As Fgf8 expression becomes established, Otx2 expression weakens, but remains in cells abutting the Fgf8 expression domain. ⋯ Thus, these experiments provide evidence that FGF8 can regulate both morphogenesis and patterning of the rostral prosencephalon (telencephalic and optic vesicles). FGF8 beads can induce midline properties (e.g. a sulcus) and can modulate the specification and differentiation of adjacent tissues. We suggest that some of these effects are through regulating the expression of homeobox genes (Otx2 and Emx2) that are known to participate in forebrain patterning.
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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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The role of Orphanin-FQ/nociceptin in synaptic plasticity was assessed by its potency in modulating kindling epileptogenesis in vivo, and feed-forward inhibition in hippocampal recordings in vitro. In addition, a specific rabbit antiserum against this peptide was obtained and the immunohistochemical distribution of nociceptin was determined in rat brain slices. After the establishment of kindling epilepsy, by daily electrical stimulation of the piriform cortex, the i.c.v. injection of nociceptin, 20 min before the kindling stimulation, was not able to block the generation of the generalized seizures, nor to alter their duration. ⋯ By single pulses applied over the Schaffer collaterals, we found that synaptic transmission was facilitated onto CA1, but using a paired-pulse protocol, we found that nociceptin potentiated feed-forward inhibition. The immunohistochemical data show that nociceptin is expressed in limbic cortical regions, including the piriform cortex and the hippocampus. Our results demonstrate that nociceptin exerts a modulatory role in limbic excitability and suggest that it provides an inhibitory control in the development of epilepsy by possibly inhibiting the spread of excitation through the system, by favoring feed-forward inhibition.