Brain research
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The induction of gene expression has been correlated with long-lasting neuronal plasticity and long-term memory (LTM) formation. The fast activation of constitutive transcription factors by signaling mechanisms is thought to be the link between synaptic events and gene expression. However, only one constitutive transcription factor, CREB, has been shown to play a key role in several memory paradigms, both in vertebrates and invertebrates. ⋯ The kinetics of activation was studied and two waves of DNA-binding activity were found, similar to the time course described in other systems. NFkappa-B activation after training was also found in synaptosomal extracts. The latter result supports the hypothesis of a novel synapse-to-nucleus signaling system, in which the transcription factor is locally activated by synaptic events and then transported to the nucleus.
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Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury.
Chronic constriction injury (CCI) to peripheral nerve causes a painful neuropathy in association with a process of axonal degeneration and endoneural remodeling that involves macrophage recruitment and local increase in extracellular proteases and tumor necrosis factor alpha (TNF-alpha). Cell surface activation of TNF-alpha from its transmembrane precursor, as well as sequestration of TNF-alpha receptors II and I, is performed by the zinc-dependent endopeptidase family of matrix metalloproteinases (MMPs). Among TNF-alpha-converting MMPs, basal lamina degrading gelatinases are thought to play a role in sciatic nerve injury. ⋯ This peak is marked by the increase in active soluble 17 kDa TNF-alpha and by gelatinase A (MMP-2) upregulation. These observations suggest that there is a pathogenic role for the TNF-alpha-converting function of MMP-2 in painful CCI neuropathy. We conclude that severe nerve injury induces MMPs, TNF-alpha and TNFRI, which interactively control the privileged endoneurial environment and the pathogenesis of the painful neuropathies associated with the macrophage-dependent processes of Wallerian degeneration.
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The goal of the present study was to determine the role of basal synthesis/release of nitric oxide on the basal permeability characteristics of the blood-brain barrier to various sized molecules in vivo. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier was quantitated by calculating the clearance of fluorescent-labeled albumin (mol.wt.=69,000 Da; FITC-albumin), fluorescent-labeled dextran (mol.wt.=10,000 Da; FITC-dextran-10K) or sodium fluorescein (mol.wt.=376; NaFl) in the absence and presence of an inhibitor of nitric oxide synthase (N(G)-monomethyl-L-arginine; L-NMMA; 10 and 100 microM). ⋯ Although topical application of L-NMMA produced constriction of pial arterioles, L-NMMA did not alter the permeability characteristics of the blood-brain barrier to FITC-albumin, FITC-dextran-10K or NaFl. Further, the adherence of leukocytes to the endothelium appeared to be similar while suffusing with vehicle and L-NMMA (100 microM). Thus, the findings of the present study suggest that while basal synthesis/release of nitric oxide may play an important role in regulation of basal tone of cerebral blood vessels, it does not appear that basal synthesis/release of nitric oxide plays an important role in maintaining the integrity of the blood-brain barrier to large or small molecules.
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Inflammation induces an upregulation of sodium channels in sensory neurons. This most likely occurs as a result of the retrograde transport of cytochemical mediators released during the inflammatory response. The purpose of this study was to determine the effect of the subcutaneous administration of one such mediator, nerve growth factor (NGF), on the production of sodium channels in neurons of the rat dorsal root ganglion. ⋯ Sodium channel labeling was found to increase dramatically in the small neurons of the associated dorsal root ganglia beginning at 23 h, reached maximum intensity by 1 week, and persisted for up to 3 months post-injection. Pre-blocking NGF with anti-NGF prevented the NGF-induced decrease in paw withdrawal latencies and significantly reduced the intensity of sodium channel labeling. The results indicate that NGF is an important mediator both in the development of acute hyperalgesia and in the stimulation of sodium channel production in dorsal root ganglia during inflammation.
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Clinical Trial
Duration and distribution of experimental muscle hyperalgesia in humans following combined infusions of serotonin and bradykinin.
The present study examined distribution and duration of muscle hyperalgesia to pressure stimuli after intramuscular bolus-infusions of serotonin (5-HT, 20 nmol) and bradykinin (BKN, 10 nmol) in 10 volunteers. Infusions were given into the tibialis anterior (TA) muscle over 20 s with an inter-infusions interval of 3 min. Infusions of isotonic saline (NaCl, 0.9%) were given as control. ⋯ Serotonin may enhance the effect of bradykinin in producing experimental muscle pain and muscle hyperalgesia to mechanical stimuli. The combination of serotonin and bradykinin can produce muscle hyperalgesia, lasted for up to 40 min and located within the muscle. No widespread hyperalgesia to the ankle and other leg (tested at 10 cm below the patella and ankle) was observed suggesting a predominant peripheral origin of the experimentally induced hyperalgesic stage.