Molecular and cellular neurosciences
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Mol. Cell. Neurosci. · Apr 2007
Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1.
Nerve growth factor (NGF) induces an acute sensitization of nociceptive DRG neurons, in part, through sensitization of the capsaicin receptor TRPV1 via the high affinity trkA receptor. The mechanisms linking trkA and TRPV1 remain controversial with several candidate signaling pathways proposed. Utilizing adult rat and mouse DRG neurons and CHO cells co-expressing trkA and TRPV1, we have investigated the signaling events underlying acute TRPV1 sensitization by NGF combining biochemical, electrophysiological, pharmacological, mutational and genetic knockout approaches. ⋯ Biochemical analysis of p42/p44 and Akt phosphorylation confirmed the specificity of pharmacological agents and trkA mutants. Finally, NGF sensitization of capsaicin responses was greatly reduced in neurons from p85alpha (regulatory subunit of PI3K) null mice. These data strongly suggest that PI3K and MAPK pathways, but not the PLC pathway underlie the acute sensitization of TRPV1 by NGF.
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Mol. Cell. Neurosci. · Nov 2006
Comparative StudyInvolvement of DRG11 in the development of the primary afferent nociceptive system.
During development, dorsal root ganglia (DRG) neurons differentiate in various subpopulations, nociceptive neurons belonging in the small-diameter class. This study addresses the role played by DRG11, a transcription factor expressed in the spinal area of projection of small-diameter DRG neurons, in the development of the primary afferent system. The various subclasses of DRG neurons were compared between wild-type and Drg11(-/-) mice at embryonic and postnatal life. ⋯ Innervation by small DRG neurons was impaired in cutaneous, visceral and deep tissues. Large DRG neurons were not affected. The data point to a role for DRG11 in early postnatal survival of normally generated small primary afferent neurons innervating various kinds of peripheral tissues, which would explain the nociceptive deficits observed in Drg11-null mutant mice.
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Mol. Cell. Neurosci. · May 2006
Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain.
In the adult mouse forebrain, large numbers of neuronal precursors, destined to become GABA- and dopamine-producing interneurons of the olfactory bulb (OB), are generated in the subventricular zone (SVZ). Although this neurogenic system represents a potential reservoir of stem and progenitor cells for brain repair approaches, information about the survival and differentiation of SVZ-derived cells in ectopic brain regions is still fragmentary. ⋯ This procedure allowed the purification of neuronal precursors expressing TUJ1, DCX and GAD65/67. Transplantation of these cells led again to the generation of the same two glial cell types, showing that committed interneuron precursors undergo glial differentiation outside their normal environment.
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Mol. Cell. Neurosci. · Mar 2006
Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain.
Conditional mouse knock-outs provide an informative approach to drug target validation where no pharmacological blockers exist or global knock-outs are lethal. Here, we used the Cre-loxP system to delete BDNF in most nociceptive sensory neurons. Conditional null animals were healthy with no sensory neuron loss. ⋯ NGF-induced thermal hyperalgesia was halved, and mechanical secondary hyperalgesia caused by intramuscular NGF was abolished. By contrast, neuropathic pain behavior developed normally. Nociceptor-derived BDNF thus plays an important role in regulating inflammatory pain thresholds and secondary hyperalgesia, but BDNF released only from nociceptors plays no role in the development of neuropathic pain.
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Mol. Cell. Neurosci. · Dec 2005
Selective activation of G-protein coupled receptors by volatile anesthetics.
Ion channels and ionotropic neurotransmitter receptors have long been investigated as the principle targets of inhaled volatile anesthetics (VAs), but emerging evidence suggests that G-protein coupled receptors (GPCRs) might also directly interact with VAs. To survey the extent of interaction between VAs and diverse GPCRs, we have turned to the 1000+ member family of olfactory receptors (ORs), taking advantage of their unique expression pattern of a single OR per neuron. ⋯ Together with evidence of antagonism by odorants, this selective activation strongly implicates a direct action of VAs upon particular olfactory receptors. The finding that VAs stimulate nearly 8% of olfactory GPCRs suggests that probing related Class A GPCRs may reveal a pool of VA targets whose altered signaling contributes to anesthetic effects.