It is recently evident that the central nervous system (CNS) exerts important regulatory influences on gastrointestinal (GI) motility. CNS neuropeptides appear to be especially important in central regulation of motility. Certain of the centrally-distributed """"""""brain-gut"""""""" neuropeptides administered exogenously have dramatic effects in the motility and reflexes of the GI tract. The specific sites or mechanisms through which these peptides affect the gut have not been determined. Neuropeptides can act at a discrete sites in affecting GI motor function: the brain the neurons of the enteric nervous system, the smooth muscle of the gut, and, as only very recently demonstrated, the spinal cord. It is the hypothesis of this proposal that the """"""""brain-gut"""""""" peptides act through chemosensitive sites in the brain and spinal cord to serve as physiological or pharmacological modulators of GI motility. We propose to focus our studies on the central effects of mammalian bombesin agastrin releasing peptide; GRP), corticotropin releasing hormone (CRF) and certain opioid neuropeptides on (a) ongoing and (b) evoked reflex activity of the gut. Our approach will initially involve administration of neuropeptides into the brain and into the spinal subarachnoid space to define the chemosensitive sites fundamentally involved in the control of GI motility. The endpoints to be studied are all standard in our laboratory and include determination of gastric emptying and small and large bowel transit, stomach and intestinal intraluminal pressure in the rat as will as GI transit in the mouse. In addition, a recently developed model proposed for study is the evoked gastrocolic reflex in the rat. The major techniques that will be employed to dissect the peptidergic pathways that control the gut include: (a) microinjections into specific brain locations and cord levels and (b) transection of the spinal cord at various levels so that the influence of the sympathetic or parasympathetic gut innervation can be determined. Our recent work provides evidence that peptide sensitive sites in the spinal cord can be distinguished anatomically, pharmacologically and functionally from those in the brain. Knowledge of the sites and functions of the neuronal """"""""brain-gut"""""""" peptides will provide new information about central nervous system-gut interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK033547-04
Application #
3231962
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1984-12-01
Project End
1993-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
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Wire, W S; Kramer, T H; Burks, T F (1989) In vitro comparison of efficacies of ""full"" kappa opioid agonists. Proc West Pharmacol Soc 32:177-81
Burks, T F; Fox, D A; Hirning, L D et al. (1988) Regulation of gastrointestinal function by multiple opioid receptors. Life Sci 43:2177-81
Heyman, J S; Porreca, F (1987) Intrathecal beta-funaltrexamine (beta-FNA) is a long acting agonist in the mouse abdominal stretch test. Proc West Pharmacol Soc 30:209-10
Burks, T F; Galligan, J J; Hirning, L D et al. (1987) Brain, spinal cord and peripheral sites of action of enkephalins and other endogenous opioids on gastrointestinal motility. Gastroenterol Clin Biol 11:44B-51B

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