There are a large number of transmitters and receptors contained in enteric nerves. The interaction of nerves, and the substances they release, with other nerves and with intestinal smooth muscle is poorly understood. The principal aims of this proposal are to determine some of the specific neural connections in the myenteric plexus which coordinate propulsive contractions in the small intestine. This will be accomplished in 3 projects. The first project will use intracellular electrophysiological techniques to study drug receptors on neuronal cell bodies by measuring changes in membrane potential following drug application, and on nerve terminals by measuring drug-induced changes in synaptic potentials. Preliminary data indicate that groups of drug receptors may be co-localized on the soma and nerve terminals of specific subsets of neurons and receptor neurons. These studies will focus on opioid, 5-HT, and alpha2 adrenergic receptors. The electrophysiologically and pharmacologically identified neurons will be marked with an intracellular dye and the tissues processed for immunohistochemical localization of the neuropeptides substance P and vasoactive intestinal peptide in neurons. The second project will use pharmacological and microsurgical techniques to determine the transmitters and pathways involved in the peristaltic reflex. The third project will use intracellular electrophysiological techniques to record from myenteric neurons during peristalsis. The results of these three projects would describe, in detail, the neural circuitry underlying reflex contractions of the small intestine. Specific functions would be assigned to identified neurons and the actions of drugs could be attributed to an effect on specific neurons. These data would have applications to basic neurobiology in describing the functions of a complete nerve network. Additional benefits could be derived from the development of therapies for disorders of gastrointestinal motility involving enteric nerves. These disorders include Hirshprung's disease, colitis and ileitis, the irritable bowel syndrome and neuropathies associated with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DK040210-01A2
Application #
3463426
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1990-05-01
Project End
1995-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Galligan, J J (1999) Nerve terminal nicotinic cholinergic receptors on excitatory motoneurons in the myenteric plexus of guinea pig intestine. J Pharmacol Exp Ther 291:92-8
Yunker, A M; Paupore, E J; Galligan, J J (1999) C-Fos in enteric nerves after extrinsic denervation of guinea pig ileum. J Surg Res 82:324-30
LePard, K J; Messori, E; Galligan, J J (1997) Purinergic fast excitatory postsynaptic potentials in myenteric neurons of guinea pig: distribution and pharmacology. Gastroenterology 113:1522-34
Yunker, A M; Galligan, J J (1996) Endogenous NO inhibits NANC but not cholinergic neurotransmission to circular muscle of guinea pig ileum. Am J Physiol 271:G904-12
Zhou, X; Galligan, J J (1996) P2X purinoceptors in cultured myenteric neurons of guinea-pig small intestine. J Physiol 496 ( Pt 3):719-29
Bertrand, P P; Galligan, J J (1995) Signal-transduction pathways causing slow synaptic excitation in guinea pig myenteric AH neurons. Am J Physiol 269:G710-20
Pan, H; Galligan, J J (1994) 5-HT1A and 5-HT4 receptors mediate inhibition and facilitation of fast synaptic transmission in enteric neurons. Am J Physiol 266:G230-8
Yunker, A M; Galligan, J J (1994) Extrinsic denervation increases NADPH diaphorase staining in myenteric nerves of guinea pig ileum. Neurosci Lett 167:51-4
Galligan, J J; Bertrand, P P (1994) ATP mediates fast synaptic potentials in enteric neurons. J Neurosci 14:7563-71
Bertrand, P P; Galligan, J J (1994) Contribution of chloride conductance increase to slow EPSC and tachykinin current in guinea-pig myenteric neurones. J Physiol 481 ( Pt 1):47-60

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