The long-term goal of this research program is to define the neurochemical mechanisms that mediate the regulation of food intake by the parabrachial nucleus (PBN) in the pons. This application focuses on the role of mu-opioid receptors (muOR) in the PBN in neuronal processes that increase feeding. In preliminary data, infusing the muOR agonist DAMGO into the lateral PBN (LPBN) increased food intake in a behaviorally specific manner. Conversely, acute blockade of muORs reduced feeding. Neuropeptide FF (NPFF) both opposed and mimicked the actions of DAMGO. Immunocytochemical data and analysis of DAMGO stimulated G-protein coupling by [35S]GTPgammaS autoradiography suggested a role for the external lateral subnucleus of the LPBN in these behavioral actions. The proposed studies will use behavioral, pharmacological, immunotoxic, immunocytochemical, autoradiographic, and cellular techniques to: 1) define more precisely the anatomical site and opioid receptor mechanisms for the orexigenic action of DAMGO; 2) assess whether acute and chronic irreversible antagonism of parabrachial uORs reduce food intake; 3) determine whether preferred foods enhances the actions of uOR agonists and antagonists; 4) test the hypothesis that immunotoxic lesions of cells in the LPBN that express uORs will produce hyperphagia; 5) analyze the effects of food restriction and palatable food on opioid receptor mediated G-protein coupling, cfos activation and CREB phosphorylation and on constitutive levels of CREB in the PBN; 6) analyze the interactions of serotonergic, NPFFergic and GABAergic mechanisms with muORs in order to being elucidating the neurochemical organization of parabrachial circuits that regulate feeding; and 7) use sham feeding and flavor preference/aversion conditioning to characterize the behavioral adjustments produced by manipulating muORs, and to test the hypothesis that infusions of DAMGO into the PBN are positively reinforcing. In concert, these studies should provide new data for defining the mechanisms by which opioid neuropeptides in the PBN serve the regulation of food intake. The results should help to define the neurochemical interactions within the circuitry of this brainstem region that direct feeding, specifically, and appetitive reward more generally. Thus, the data may be useful for elaborating novel approaches for treating obesity, eating disorders and behaviors underlying self-administration of substances such as drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067648-05
Application #
7456585
Study Section
Special Emphasis Panel (ZRG1-NMB (02))
Program Officer
Yanovski, Susan Z
Project Start
2004-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2010-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$305,250
Indirect Cost
Name
Drexel University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chaijale, Nayla N; Aloyo, Vincent J; Simansky, Kenny J (2013) The stereoisomer (+)-naloxone potentiates G-protein coupling and feeding associated with stimulation of mu opioid receptors in the parabrachial nucleus. J Psychopharmacol 27:302-11
Denbleyker, M; Nicklous, D M; Wagner, P J et al. (2009) Activating mu-opioid receptors in the lateral parabrachial nucleus increases c-Fos expression in forebrain areas associated with caloric regulation, reward and cognition. Neuroscience 162:224-33
DiPatrizio, Nicholas V; Simansky, Kenny J (2008) Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci 28:9702-9
Dipatrizio, Nicholas V; Simansky, Kenny J (2008) Inhibiting parabrachial fatty acid amide hydrolase activity selectively increases the intake of palatable food via cannabinoid CB1 receptors. Am J Physiol Regul Integr Comp Physiol 295:R1409-14
Chaijale, Nayla N; Aloyo, Vincent J; Simansky, Kenny J (2008) A naloxonazine sensitive (mu1 receptor) mechanism in the parabrachial nucleus modulates eating. Brain Res 1240:111-8
Burbassi, Silvia; Aloyo, Vincent J; Simansky, Kenny J et al. (2008) GTPgammaS incorporation in the rat brain: a study on mu-opioid receptors and CXCR4. J Neuroimmune Pharmacol 3:26-34
Ward, Heather G; Simansky, Kenny J (2006) Chronic prevention of mu-opioid receptor (MOR) G-protein coupling in the pontine parabrachial nucleus persistently decreases consumption of standard but not palatable food. Psychopharmacology (Berl) 187:435-46