Neuroscience
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The role of the dorsal columns in neuropathic behavior: evidence for plasticity and non-specificity.
Despite conflicting clinical and experimental evidence, textbook description of somatic sensations continues to follow a rigid dichotomy based on the concept that pain sensation is transmitted cephalad primarily through anterolateral pathways, while touch is mediated through the dorsal column pathway. This study provides an example of the dynamic rerouting in the transmission of the nociceptive signals following injuries to the peripheral and central processes of sensory neurons. In two rat models for mononeuropathy, the chronic constriction injury model [Bennett, G. ⋯ Furthermore, these results shade doubts on the validity of the concept of segregation of pathways involved in the transmission of neuropathic manifestations. Therefore, principles governing acute pain transmission are not necessarily applicable to chronic pain situations. The latter conditions seem to engage other available pathways to reestablish the pain signaling system.
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Protein kinase C isoforms including the alpha isozyme have been implicated in morphine tolerance. In the present study, we examined the effect of intrathecal delivery of an antisense oligonucleotide targeting rat protein kinase Calpha mRNA on the expression of spinal protein kinase Calpha isozyme and spinal morphine tolerance. Continuous intrathecal infusion of rats with morphine produced an increase in paw withdrawal threshold to thermal stimulation on day 1, which disappeared by day 5. ⋯ The antisense also attenuated protein kinase C-mediated phosphorylation in spinal cord. These results demonstrate that selective reduction in the expression of the spinal protein kinase Calpha isozyme followed by a decrease of local protein kinase C-mediated phosphorylation will reverse spinal morphine infusion-induced tolerance. This finding is consistent with the view that tolerance produced by morphine infusion is dependent upon an increase in phosphorylation by protein kinase C, and also it emphasizes that the protein kinase Calpha isozyme and its activation in spinal cord may specifically participate in the phenomenon of opiate tolerance.
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Glutamate-gated ion channels are widely expressed in neurons where they serve a host of cellular functions. An appealing, but yet unexplored, way to delineate the functions of particular glutamate receptor subtypes is to direct the expression of dominant-negative and gain-of-function mutant subunits. We tested the ability of two dominant-negative subunits, an alpha-amino-3-hydroxy-5-methyl-isoxazolproprionic acid receptor subunit and a kainate receptor subunit, to silence recombinant and neuronal glutamate receptors. ⋯ When expressed in cerebellar granule cells, the dominant-negative subunits silenced native channels in a subtype-specific fashion. Immunocytochemical staining of control and transfected neurons, as well as studies with a gain-of-function glutamate receptor-1 mutant, indicated that the mutant subunits were expressed at levels roughly equal to the total abundance of related native subunits, and both dominant-negatives suppressed native channel expression 60-65% when tested 24 h post-transfection. If co-assembly of the mutant subunits with related native subunits is combinatorial, this level of suppression gives receptor half-lives of approximately 20 h.
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Mechanisms underlying neuropathic pain states are poorly understood. We have compared mechanisms mediating enhanced nociception of four established models of neuropathic pain produced by very different types of insults to the peripheral nervous system: streptozotocin-induced hyperalgesia, a model of diabetic (metabolic) peripheral neuropathy, vincristine-induced hyperalgesia, a model of chemotherapeutic agent (toxic) peripheral neuropathy, and chronic constriction injury and partial nerve ligation, models of trauma-induced painful neuropathies. All four models resulted in prolonged mechanical hyperalgesia (>30% decrease in mechanical nociceptive threshold) and allodynia (detected by 10-209-mN-intensity von Frey hairs). ⋯ None of these second messengers nor the NMDA receptor, which can contribute to peripheral sensitization of nociceptors, contributed to chronic constriction injury- and partial nerve ligation-induced hyperalgesia. In all four models the hyperalgesia was not antagonized by peripheral administration of a mu-opioid agonist. Our findings support the presence of a common abnormality in second messenger signaling in the periphery to the maintenance of two very different models of non-traumatic neuropathic pain, not shared by models of trauma-induced neuropathic pain.
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The present study analyzed using immunohistochemical labeling the distribution and co-localization of nitric oxide synthase (NOS), cocaine- and amphetamine-regulated transcript peptide (CARTp) and pituitary adenylate cyclase activating polypeptide (PACAP) with choline acetyltransferase (ChAT)-immunoreactive fibers in the guinea-pig stellate ganglia. ChAT-immunoreactive fibers make pericellular baskets around virtually all stellate ganglia neurons. ⋯ No evidence of co-localization of NOS, PACAP and CARTp was obtained. These results indicate that NOS, PACAP and CARTp are present in distinct preganglionic axons innervating the guinea-pig stellate ganglia.