Neuroscience
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The A7 catecholamine cell group in the dorsolateral pontine tegmentum constitutes an important part of the descending pathways that modulate nociception. Evidence from immunocytochemical studies demonstrate that noradrenergic A7 neurons are densely innervated by GABA terminals arising from GABA neurons that are located in the dorsolateral pontine tegmentum medial to the A7 cell group. GABA(A) receptors are also located on the somata and dendrites of noradrenergic A7 neurons. ⋯ These findings suggest that noradrenergic neurons in the A7 cell group are tonically inhibited by local GABA neurons. Furthermore, these findings suggest that inhibition of GABA(A) receptors located on spinally-projecting A7 noradrenergic neurons disinhibits, or activates, two populations of A7 neurons that have opposing effects on nociception. One of these populations facilitates nociception by an action mediated by alpha(1)-adrenoceptors in the spinal cord dorsal horn and the other population inhibits nociception by an action mediated by alpha(2)-adrenoceptors.
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The slit genes have recently been found to encode proteins with a conserved chemorepulsive activity for axons in invertebrates and vertebrates. We have determined the expression pattern of a slit gene in Xenopus embryos. ⋯ Using a myc-tagged secreted Slit protein, we confirmed the binding of Slit to Roundabout expressed on the cell surface. These results confirm Slit-Roundabout interactions and the biochemical properties of Slit and Roundabout proteins, and further support the idea that Slit may guide axon projections in multiple regions of the embryo.
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Several genetic mouse models of differential sensitivity to opioids have been used to investigate the mechanisms underlying individual variation in responses to opioids. The CXBK mice are inbred recombinant mice which have a lower level of mu(1)-opioid receptors than their parental strain. Endomorphin-1 and endomorphin-2 are endogenous opioid peptides that are highly selective for mu-opioid receptors, while beta-endorphin, which is also an endogenous opioid peptide, is non-selective for mu-, delta- and putative epsilon-opioid receptors. ⋯ However, there was no strain difference in the stimulation of guanosine-5'-o-(3-[35S]thio)triphosphate binding induced by 10 microM of the selective delta(1)-opioid receptor agonist [D-Pen(2,5)]enkephalin, delta(2)-opioid receptor agonist [D-Ala(2)]deltorphin II or kappa-opioid receptor agonist U50,488H. The results indicate that the G-protein activation by endomorphin-1 and endomorphin-2 in the mouse pons/medulla is mediated by both mu(1)- and mu(2)-opioid receptors. Moreover, beta-endorphin-induced G-protein activation in the mouse pons/medulla is, in part, mediated by mu(2)- and putative epsilon-, but not by mu(1)-opioid receptors.
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Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone's abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide's levels in the hippocampus have not yet been determined. ⋯ Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration. Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide's expression in the hypothalamus is influenced by neuroendocrine challenges.
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Sensory circumventricular organs bordering the anterior third cerebral ventricle, the subfornical organ and the organum vasculosum laminae terminalis, lack blood-brain barrier characteristics and are therefore accessible to circulating peptides like endothelins. Astrocytes of the rat subfornical organ and organum vasculosum laminae terminalis additionally showed immunocytochemical localization of endothelin-1/endothelin-3-like peptides, possibly acting as circumventricular organ-intrinsic modulators. Employing [125I]endothelin-1 as radioligand, quantitative autoradiography demonstrated specific binding sites throughout the rat organum vasculosum laminae terminalis and subfornical organ, and competitive displacement studies revealed expression of both ET(A) and ET(B) receptor subtypes for either circumventricular organ. ⋯ In summary, the results indicate that endothelin(s) interact(s) with circumventricular organ astrocytes. Competitive receptor binding techniques using brain tissue sections as well as a fura-2 loaded primary cell culture system of the subfornical organ and organum vasculosum laminae terminalis demonstrate glial expression of functional ET(A) and ET(B) receptors, with calcium as intracellular messenger emerging primarily from intracellular stores. Endothelin(s) of both circulating and circumventricular organ-intrinsic origin may afferently transfer information important for cardiovascular homeostasis to circumventricular organs serving as "windows to the brain".