Neuroscience
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The selective and potent aminopeptidase N inhibitor [125I]RB 129 has been used for the radioautographic localization of this enzyme in rat brain, spinal cord and intestine. Brain microvessels and intestine brush-border cells were shown to present a high concentration of aminopeptidase N. Moreover, a labeling of various brain structures was observed. ⋯ This iodinated probe could allow the ex vivo and in vivo localization of aminopeptidase N in various tissues to be investigated and may also be used to evaluate quantitative changes in aminopeptidase N expression in pathological situations. Aminopeptidase N, which preferably removes NH2-terminal neutral amino acids from peptides, has probably a host of substrates. Nevertheless, a certain in vivo selectivity could be achieved by the presence of the enzyme in structures where the peptide effector and its receptors are also co-localized.
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Research using animal models of neuropathic pain has revealed sympathetic sprouting onto dorsal root ganglion cells. More recently, sensory fibre sprouting onto dorsal root ganglion cells has also been observed. Previous work in our laboratory demonstrated persistent sympathetic fibre sprouting in the skin of the rat lower lip following sensory denervation of this region. ⋯ These results indicate that sympathectomies lead to transient changes in substance P-immunoreactive fibre innervation and neurokinin-1 receptor expression in rat lower lip skin. The effects are most prominent in the lower dermis probably due to a greater local concentration of nerve growth factor in this region. The plasticity of the interactions between sensory and sympathetic fibres may prove important in the regulation of skin microcirculation and in the generation of painful sensations under normal conditions or following peripheral nerve injuries.
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Glutamate transporter-1 (GLT-1) is responsible for the largest proportion of glutamate transport in the brain and the density of GLT-1 molecules inserted in the plasma membrane is highest in regions of high demand. Previous electron microscopic studies in the hippocampus and cerebellum have shown that GLT-1 is concentrated both in the vicinity of and at considerable distance from the synaptic cleft [Chaudry et al., Neuron 15 (1995) 711-721], but little is known about its distribution in the neocortex. We therefore studied the spatial relationships between elements expressing the presynaptic marker synaptophysin and those containing GLT-1 in the rat cerebral cortex using confocal microscopy. ⋯ In sections double-labeled for GLT-1 and the vesicular GABA transporter, codistribution analysis revealed that 27% of pixels detecting GLT-1 overlapped with those revealing the vesicular GABA transporter. The remarkable 'synaptic' localization of GLT-1 provides anatomical support for the hypothesis that in the cerebral cortex GLT-1 contributes to shaping fast, point-to-point, excitatory synaptic transmission. Moreover, the considerable fraction of GLT-1 immunoreactivity localized at sites distant from axon terminals supports the notion that glutamate spillout occurs also in the intact brain and suggests that 'extrasynaptic' GLT-1 regulates the diffusion of glutamate escaped from the cleft.
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The role of nociceptin, the endogenous ligand for the opioid receptor-like (ORL1) receptor, in nociceptive processing is controversial. Most studies demonstrate hyperalgesia following supraspinal administration, analgesia following intrathecal and peripheral administration at higher doses, and hyperalgesia following intrathecal and peripheral application at lower doses. The present study investigates the effect of nociceptin on synovial plasma extravasation and its ability to modulate 5-hydroxytryptamine-induced synovial plasma extravasation using the rat knee joint model of inflammation. ⋯ Nociceptin at concentrations up to 1 nM enhances 5-hydroxytryptamine-induced synovial plasma extravasation (up to 50%) and nociceptin at concentrations above 100 nM inhibits 5-hydroxytryptamine-induced synovial plasma extravasation (down to 45%). The novel, selective ORL1 receptor antagonist J-113397 potently inhibits the pro-inflammatory effect of nociceptin, but only partly inhibits, at higher concentrations, the anti-inflammatory effects of nociceptin. These findings demonstrate a dose-dependent bi-directional effect of nociceptin on inflammatory processes and may indicate a target for novel therapeutics.
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We examined the effects of systemic administration of a GABA(B) receptor agonist, baclofen, or antagonist, phaclofen, on the expression of c-Fos protein induced 3h after electrical stimulation of the trigeminal ganglion at low (0.1 mA) or high intensities (1.0 mA) in the urethane-anesthetized rat. In saline-treated rats, 10 min stimulation of the trigeminal ganglion induced c-Fos-immunopositive neurons throughout the full extent of the ipsilateral superficial layers of the trigeminal nucleus caudalis, and dorsal or dorsomedial part of the nuclei rostral to obex (trigeminal nucleus principalis, dorsomedial nucleus of trigeminal nucleus oralis and dorsomedial nucleus of trigeminal nucleus interpolaris). Animals stimulated at 1.0 mA induced a significantly higher number of labeled neurons in all the trigeminal sensory nuclei than animals stimulated at 0.1 mA. ⋯ These results indicate that the expression of c-Fos in the trigeminal sensory nucleus is differentially regulated through GABAB receptors in a manner that is dependent on the nucleus and the type of primary afferents that are activated by different stimulus intensities. Systemic administration of baclofen could inhibit both nociceptive and non-nociceptive sensory activity in the trigeminal sensory nucleus. Systemic administration of phaclofen could enhance nociceptive sensory activity but not non-nociceptive activity.