Neuroscience
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Many studies have shown that activation and increase in the number of astrocytes and microglia in the spinal cord participate in the initiation and maintenance of neuropathic pain, but little attention has been paid to the responses of neural progenitor cells to peripheral nerve injury. Nestin, a class VI intermediate filament protein, is expressed both in neuronal and glial progenitors as well as in their common precursors; and nestin-positive cells appear in the brain and spinal cord following various forms of damage to these regions. To clarify the responses of neural progenitor cells to nerve injury, we applied L5 spinal nerve transection (L5-SNT) to nestin-promoter GFP (pNestin-GFP) transgenic mice to narrow the target to them. ⋯ On the other hand, the activation and increase in number of microglia and astrocytes are restricted to the superficial layer of the dorsal horn, the central terminal of injured primary afferent fibers. Purinergic P2X agonist α, β-MeATP increased [Ca(2+)]i in nestin-positive cells in the superficial layer ipsilateral to nerve injury and P2 receptor antagonists suramin and pyridoxalphosphate-6-azophenyl-2,4-disulphonic acid (PPADS) blocked the expression and elongation of pNestin-GFP fibers in the slice culture of the spinal cord. These results with pNestin-GFP transgenic mice demonstrate that nestin-positive cells proliferate in the dorsal horn in response to peripheral nerve injury and suggest that ATP may contribute to the expression of nestin and activation of neural progenitor cells after nerve injury.
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Acid sensing ion channels (ASIC) are found in sensory neurons, including those that innervate muscle tissue. After peripheral inflammation there is an increase in proton concentration in the inflamed tissue, which likely activates ASICs. Previous studies from our laboratory in an animal model of muscle inflammation show that hyperalgesia does not occur in ASIC3 and ASIC1 knockout mice. ⋯ The mean pH-evoked current amplitudes were significantly increased in muscle sensory neurons from inflamed mice (pH 5.0, 3602 ± 470 pA) in comparison to the controls (pH 7.4, 1964 ± 370 pA). In addition, the biophysical properties of ASIC-like currents were altered after inflammation. Changes in ASIC channels result in enhanced responsiveness to decreases in pH, and likely contribute to the increased hyperalgesia observed after muscle inflammation.
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Many features of the suprachiasmatic nucleus (SCN) are the same in diurnal and nocturnal animals, suggesting that differences in phase preference are determined by mechanisms downstream from the SCN. Here, we examined this hypothesis by characterizing rhythmic expression of Period 1 (PER1) and Period 2 (PER2) in several extra-SCN areas in the brains of a diurnal murid rodent, Arvicanthis niloticus (grass rats). In the shell of the nucleus accumbens, dorsal striatum, piriform cortex, and CA1 of the hippocampus, both PER1 and PER2 were rhythmic, with peak expression occurring at ZT10. ⋯ In contrast, the rhythmic expression of both PER proteins was identical in the SCN and ventral subparaventricular zone (vSPZ) of DA and NA animals. Differences in the phase of oscillators downstream from the SCN, and perhaps the vSPZ, appear to determine the phase preference of particular species, as well as that of members of a diurnal species that show voluntary phase reversals. The latter observation has important implications for the understanding of health problems associated with human shift work.
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Activation of glutamate receptors and glial cells in the spinal dorsal horn are two fundamental processes involved in the pathogenesis of various pain conditions, including neuropathic pain induced by injury to the peripheral or central nervous systems. Numerous studies have demonstrated that minocycline treatment attenuates allodynic and hyperalgesic behaviors induced by tissue inflammation or nerve injury. However, the synaptic mechanisms by which minocycline prevents hyperalgesia are not fully understood. ⋯ Minocycline ameliorated both the downregulation of glial GT expression and the activation of astrocytes induced by pSNL in the spinal dorsal horn. We further revealed that preventing deficient glial glutamate uptake at the synapse is crucial for preserving the normalized activation of NMDA receptors in the spinal sensory synapses in pSNL rats treated with minocycline. Our studies suggest that glial GTs may be a potential target for the development of analgesics.
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We studied the number, location and size of long descending propriospinal tract neurons (LDPT), located in the cervical enlargement (C3-C6 spinal levels), and short thoracic propriospinal neurons (TPS), located in mid-thoracic spinal cord (T5-T7 spinal levels), 2, 6 and 16 weeks following a moderate low thoracic (T9) spinal cord contusion injury (SCI; 25 mm weight drop) and subsequent injections of fluorogold into the upper lumbosacral enlargement (L2-L4 spinal levels). Retrograde labeling showed that approximately 23% of LDPT and 10% of TPS neurons were labeled 2 weeks after SCI, relative to uninjured animals. No additional significant decrease in number of labeled LDPT and TPS cells was found at the later time points examined, indicating that the maximal loss of propriospinal neurons in these two subpopulations occurs within the first 2 weeks post-SCI. ⋯ Interestingly, the number of labeled LDPT and TPS neurons was not significantly different following different injury severities. Although the rostro-caudal extent of the lesion site expanded between 2 and 16 weeks following injury, there was no significant difference in the number of propriospinal neurons that could be retrogradely labeled at these time points. Possible reasons for these findings are discussed.