| Grant number: | 99/12466-5 |
| Support Opportunities: | Research Projects - Thematic Grants |
| Duration: | August 01, 2000 - April 30, 2007 |
| Field of knowledge: | Biological Sciences - Pharmacology |
| Principal Investigator: | Charles Julian Lindsey |
| Grantee: | Charles Julian Lindsey |
| Host Institution: | Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil |
Abstract
Previous studies from our laboratory, employing a multidisciplinary approach, have identified the neural pathways, both by anatomical and electrophysiological approaches, as well as the receptors implicated in the pressor effect induced by bradykinin microinjection into the paratrigeminal nucleus of the rat. Specific binding sites for bradykinin have been detected, by autoradiography, in the spinal and medullary trigeminal tract, as well as in the solitary tract and paratrigeminal nuclei. Furthermore, we also confirmed the expression of the gene encoding the B2 bradykinin receptor in the rat medulla, using Molecular Biology techniques. More recently, we have found that although B1 receptor expression in the medulla, hipothalamus or spinal cord is usually undetectable, this can be markedly upregulated in rats rendered diabetic by streptozotocin or during fever induced by E. coli lipopolysaccharide. Moreover, we found that vagotomy abolishes both fever and B1 receptor expression. Such findings, taken together with the more recent literature accumulated in this field, strongly suggests that the paratrigeminal nucleus exerts an important integrative function in modulating cardiovascular, respiratory and thermoregulatory reflexes to changes in sensorial input. This view is strengthened by the fact that the nucleus receives primary afferent projections from trigeminal, glossopharyngeal and vagal nerves, and projects efferent connections to the solitary tract, as well as to the lateral and rostroventrolateral reticular, ambigus (our findings) and parabrachial nuclei. The aim of the current project is to further delineate the roles of the paratrigeminal nucleus in processing of nociceptive sensorial input and its integration with other medullary and mesencefalic structures. By use of anatomical, electrophysiological, pharmacological and neurochemical techniques, we intend to put special emphasis towards the characterization of the possible organizational relationships between afferent connections and its various specific projections to other structures. To this effect, we intend to delineate the ascending neural pathways implicated in the febrile response, with reference to the medullary nuclei (solitary tract and paratrigeminal nuclei) and thermoregulatory hypothalamic nuclei involved. A similar approach will be employed to unravel the pathways activated by nociceptive stimuli, since orofacial and visceral pain has been associated with activation of the paratrigeminal nucleus.To achieve this goal, we will make use of anatomical tools, electrophysiological recordings of neuronal activity, chemically-induced lesions of specific nuclei or structures, as well as central microinjections of specific/selective receptor agonists and antagonists, to establish the possible correlations between the behavioral, neuronal electrophysiological, cardiovascular, respiratory and thermoregulatory responses to nociceptive and febrile stimuli. The association of such changes with altered expression of neuropeptides (and of other mediators) and their respective receptors will also be probed using various molecular biology techniques. (AU)
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