The longterm goals are to understand the relationship between intestinal ion transport and the submucosal enteric neurons which play a key role in controlling this important homeostatic function. A multi-technique approach toward this goal will be used, combining intracellular recording and filling with dyes of submucosal neurones, anterograde and retrograde labelling of mucosa-to-submucosa projections, immunohistochemistry, selective denervations and tight-seal, patch clamp recording techniques. These techniques will be used to: (1) identify patterns of neuronal circuitry involving mucosal reflexes, (2) identify cellular mechanisms of neuronal excitation by putative neurotransmitters, in particular 5-HT3 receptor activation which mediates fast (ms time range) excitation and activation of receptors by substance P, muscarine, adenosine and vasoactive intestinal polypeptide (VIP) which mediate slow (s to min time range) excitation, (3) identify mechanisms of neuronal inhibition, specifically the mechanisms by which somatostatin and alpha2-adrenoceptors increase activity of single potassium channels and inhibit activity of single calcium channels. These studies will contribute significantly to basic research areas of physiology of the gastrointestinal tract as well as cellular neurophysiology in general. These studies have direct pharmacological and clinical relevance for drug use and drug development of anti-emetics to prevent chemotherapy-induced nausea and vomiting. These studies will help to identify submucosal neurones which participate in the pathophysiology of enterotoxins, such as cholera and salmonella.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS025996-04A1
Application #
3411593
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-04-01
Project End
1995-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Organized Research Units
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Vanner, S; Jiang, M M; Surprenant, A (1993) Mucosal stimulation evokes vasodilation in submucosal arterioles by neuronal and nonneuronal mechanisms. Am J Physiol 264:G202-12
Shen, K Z; Surprenant, A (1993) Common ionic mechanisms of excitation by substance P and other transmitters in guinea-pig submucosal neurones. J Physiol 462:483-501
Jiang, M M; Kirchgessner, A; Gershon, M D et al. (1993) Cholera toxin-sensitive neurons in guinea pig submucosal plexus. Am J Physiol 264:G86-94
Vanner, S; Evans, R J; Matsumoto, S G et al. (1993) Potassium currents and their modulation by muscarine and substance P in neuronal cultures from adult guinea pig celiac ganglia. J Neurophysiol 69:1632-44
Evans, R J; Surprenant, A (1993) Effects of phospholipase A2 inhibitors on coupling of alpha 2-adrenoceptors to inwardly rectifying potassium currents in guinea-pig submucosal neurones. Br J Pharmacol 110:591-6
Shen, K Z; Surprenant, A (1993) Somatostatin-mediated inhibitory postsynaptic potential in sympathetically denervated guinea-pig submucosal neurones. J Physiol 470:619-35
Shen, K Z; North, R A; Surprenant, A (1992) Potassium channels opened by noradrenaline and other transmitters in excised membrane patches of guinea-pig submucosal neurones. J Physiol 445:581-99
Evans, R J; Surprenant, A (1992) Vasoconstriction of guinea-pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP. Br J Pharmacol 106:242-9
Stack, J; Surprenant, A (1991) Dopamine actions on calcium currents, potassium currents and hormone release in rat melanotrophs. J Physiol 439:37-58
Barajas-Lopez, C; Surprenant, A; North, R A (1991) Adenosine A1 and A2 receptors mediate presynaptic inhibition and postsynaptic excitation in guinea pig submucosal neurons. J Pharmacol Exp Ther 258:490-5

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