The Journal of neuroscience : the official journal of the Society for Neuroscience
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The accumulation of amyloid beta protein (Abeta) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in Abeta begin at 6-7 months as SDS-insoluble forms of Abeta42 and Abeta40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. ⋯ From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted Abeta42 and Abeta40 increase to levels like those observed in AD brains. Coincident with the marked deposition of Abeta in brain, there is a decrease in CSF Abeta and a substantial, highly significant decrease in plasma Abeta. If a similar decline occurs in human plasma, it is possible that measurement of plasma Abeta may be useful as a premorbid biomarker for AD.
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The Shaw-like potassium channel Kv3.1, a delayed rectifier with a high threshold of activation, is expressed in the time coding nuclei of the bird auditory brainstem. In both barn owls and chickens, Kv3.1 mRNA was expressed in the cochlear nucleus magnocellularis (NM) and the nucleus laminaris (NL). Western blot analysis showed that an antibody raised against the synthetic peptide sequence of rat Kv3.1 (rKv3.1) specifically recognized the same 92 kDa protein bands in both rat and chicken synaptosomal preparations. ⋯ The major difference in localization of Kv3.1 protein between the two birds was the expression of Kv3.1 in the NM axons and terminals in the region of the barn owl NL. This location of Kv3.1 channels supports its postulated function in reducing the width of action potentials as they invade the presynaptic terminal. The presynaptic localization may be a specialization for enabling neurons in owl NM to transmit high-frequency temporal information with little jitter.
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Small diameter dorsal root ganglion (DRG) neurons, which include cells that transmit nociceptive information into the spinal cord, are known to express functional kainate receptors. It is well established that exposure to kainate will depolarize C-fiber afferents arising from these cells. Although the role of kainate receptors on sensory afferents is unknown, it has been hypothesized that presynaptic kainate receptors may regulate glutamate release in the spinal cord. ⋯ Whereas DRG cell kainate receptors were sensitive to both kainate and ATPA, most dorsal horn neurons responded only to kainate. Finally, in recordings from dorsal horn neurons in spinal slices, kainate and ATPA were able to suppress NMDA and AMPA receptor-mediated EPSCs evoked by dorsal root fiber stimulation. Together, these data suggest that kainate receptor agonists, acting at a presynaptic locus, can reduce glutamate release from primary afferent sensory synapses.
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Many clinical case reports have suggested that sustained opioid exposure can elicit unexpected, paradoxical pain. Here, we explore the possibility that (1) opioid-induced pain results from tonic activation of descending pain facilitation arising in the rostral ventromedial medulla (RVM) and (2) the presence of such pain manifests behaviorally as antinociceptive tolerance. Rats implanted subcutaneously with pellets or osmotic minipumps delivering morphine displayed time-related tactile allodynia and thermal hyperalgesia (i. e., opioid-induced "pain"); placebo pellets or saline minipumps did not change thresholds. ⋯ The subcutaneous morphine antinociceptive DRC in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats; this right shift was blocked by RVM lidocaine. The data show that (1) opioids elicit pain through tonic activation of bulbospinal facilitation from the RVM, (2) increased pain decreases spinal opioid antinociceptive potency, and (3) blockade of pain restores antinociceptive potency, revealing no change in antinociceptive signal transduction. These studies offer a mechanism for paradoxical opioid-induced pain and allow the development of approaches by which the loss of analgesic activity of opioids might be inhibited.