Neuroscience
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Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic growth factor, which also has profound effects on the diseased CNS. G-CSF has been shown to enhance recovery from neurologic deficits in rodent models of ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization of bone marrow-derived cells and by its direct actions on CNS cells. ⋯ To explain the G-CSF triggered amyloid reduction and associated reversal of cognitive impairment, several mechanisms of action were explored. (1) G-CSF was hypothesized to increase activation of resident microglia and to increase mobilization of marrow-derived microglia. The effect of G-CSF on microglial activation was examined by quantitative measurements of total microglial burden. To determine if G-CSF increased trafficking of marrow-derived microglia into brain, bone marrow-derived green fluorescent protein-expressing (GFP+) microglia were visualized in the brains of chimeric AD mice. (2) To assess the role of immune-modulation in mediating G-CSF effects, a panel of cytokines was measured in both plasma and brain. (3) To test the hypothesis that reduction of A beta deposits can affect synaptic area, quantitative measurement of synaptophysin immunoreactivity in hippocampal CA1 and CA3 sectors was undertaken. (4) To learn whether enhanced hippocampal neurogenesis was induced by G-CSF treatment, numbers of calretinin-expressing cells were determined in dentate gyrus.
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The cytokine transforming growth factor alpha (TGF alpha) has proangiogenic and proneurogenic effects and can potentially reduce infarct volumes. Therefore, we administered TGF alpha or vehicle directly into the area surrounding the infarct in female mice that received gender-mismatched bone marrow transplants from green fluorescent protein (GFP)-expressing males prior to undergoing permanent middle cerebral artery occlusion. Newborn cells were tracked with bromodeoxyuridine (BrdU) labeling and immunohistochemistry at 90 days after stroke onset. ⋯ Our results also show that infarct size was significantly reduced in animals treated with TGF alpha compared with controls. These results suggest that TGF alpha can induce angiogenesis, neurogenesis and neuroprotection after stroke. At least part of the pro-angiogenic effect appears to be secondary to the incorporation of bone marrow-derived endothelial cells into blood vessels in the infarct border zone.
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Nociceptive primary afferents have the capacity to induce a state of increased excitability in the dorsal horn neurons of the spinal cord. It is well accepted that capsaicin-sensitive C-fibers transduce noxious stimulation and acute pain and that capsaicin-insensitive A beta-fibers are responsible for touch and innocuous sensation. It has been reported that the intrathecal (i.t.) administration of prostaglandin F(2 alpha) (PGF(2 alpha)) and ATP induces mechanical allodynia via the capsaicin-insensitive primary afferent pathway. ⋯ Immunostaining of beta-galactosidase, a reporter knocked into the endogenous FP locus in FP(-/-) mice, showed that the FP receptor was co-localized with P2X(2) and P2X(3) receptors in neurons of the spinal cord. alphabeta-Methylene ATP evoked a transient or sustained [Ca(2+)](i) increase in most of the PGF(2 alpha)-responsive cells in the deeper layer of the spinal cord, and the alphabeta-methylene ATP-evoked increase was blocked by the FP receptor antagonist AL-8810 in two-thirds of the cells. Neither PGF(2 alpha) nor alphabeta-methylene ATP induced the activation of spinal microglia. The present study demonstrates that the alphabeta-methylene ATP-evoked allodynia is mediated by the FP receptor, possibly via the functional coupling between the activation of P2X(2/3) receptors on the central terminal of capsaicin-insensitive fibers and FP receptors on spinal neurons.
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The nociceptin/orphanin FQ (N/OFQ) opioid peptide receptor (NOPr) is a new member of the opioid receptor family consisting of mu, delta and kappa opioid receptors. The anti-opioid properties of its endogenous ligand, N/OFQ provide the receptor interesting potentials in symptoms and processes related to drug addiction, learning and memory, anxiety and depression, and nociception. Using target-selected N-ethyl-N-nitrosourea (ENU)-driven mutagenesis we recently generated a rat model bearing a premature stop codon in the opioid-like receptor (oprl1) gene, and here we describe the primary characterization of this novel model. ⋯ Quantitative autoradiographic mapping of mu, delta and kappa opioid receptors using [(3)H]DAMGO, [(3)H]deltorphin and [(3)H]CI-977, respectively, did not show any changes in opioid receptor binding. In conclusion, we present a novel mutant rat lacking NOPr without compensatory changes in mu, delta and kappa opioid receptors. We anticipate that this mutant rat will have heuristic value to further understand the function of NOPr.
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The aims of the present study were to establish if nalfurafine, a kappa opioid agonist, inhibits compulsive scratching in mice elicited by the s.c. administration (behind the neck) of 5'-guanidinonaltrindole (GNTI), a kappa opioid antagonist; to assess if nalfurafine prevents c-fos expression provoked by GNTI or compound 48/80, two chemically diverse pruritogens; and to distinguish on the basis of neuroanatomy, those neurons in the brainstem activated by either GNTI-induced itch or formalin-induced pain (both compounds given s.c. to the right cheek). Pretreatment of mice with nalfurafine (0.001-0.03 mg/kg s.c.) attenuated GNTI (0.3 mg/kg)-evoked scratching dose-dependently. A standard antiscratch dose of nalfurafine (0.02 mg/kg) had no marked effect on the spontaneous locomotion of mice. ⋯ In contrast to formalin, GNTI did not induce c-fos expression in the trigeminal nucleus suggesting that pain and itch sensations are projected differently along the sensory trigeminal pathway. Our data indicate that the kappa opioid system is involved, at least in part, in the pathogenesis of itch; and that nalfurafine attenuates excessive scratching and prevents scratch-induced neuronal activity at the spinal level. On the basis of our results, nalfurafine holds promise as a potentially useful antipruritic in human conditions involving itch.