Opioids are widely used for pain m management but one unwanted side effect of acute opioid administration is rapid eye movement (REM) sleep inhibition. Pain itself disrupts sleep, and sleep loss is the most common complaint of acute pain patients. Pontine choilnergic neurotransmission is a major contributor to REM sleep generation, and new data suggest that pontine GABAergic transmission and basal forebrain cholinergic transmission participate in REM sleep regulation. The long-term objectives of this renewal application are to advance scientific knowledge by specifying the cellular and molecular mechanisms through which opioids inhibit REM sleep. The four aims are unified conceptually and related to the long-term goals by focusing on opioid modulation of transmitter release and guanine nucleotide binding protein (G protein) activation. These studies focus on brain stem and forebrain regions known to regulate sleep and breathing. Novel aspects include an emphasis on the interactions of opioids with multiple transmitter systems in multiple sleep-related brain regions.
Aims 1, 2, and 3 will use in vivo microdialysis and high performance liquid chromatography. Opioids will be administered systemically and, in separate experiments, directly into brain regions of interest by reverse dialysis. Concentration-response and antagonist blocking studies will evaluate receptor mediation of opioid effects.
Aim 4 will use in vitro [35S]GTPgammaS autoradiography to examine the interaction of opioids with other sleep-modulatory neurotransmitters at the level of G protein activation.
Aim 1 will test the hypothesis that opioids decrease acetylcholine (ACh) release in medullary hypoglossal nucleus.
Aim 2 will test the hypothesis that basal forebrain opioid administration decreases basal forebrain ACh release.
The Aim 3 hypothesis is that opioids decrease gamma aminobutyric acid (GABA) release in REM sleep-regulating regions of the pontine reticular formation.
Aim 4 will test the hypothesis that opioids alter G protein activation by muscarinic cholinergic agonists and by the novel hypothalamic peptide hypocretin-1/orexin-A.
Aim 4 will specify whether combined agonist activation of G proteins in sleep-related nuclei is fully additive, partially additive, or non-additive.
Aim 4 will permit inferences concerning activation of independent or common G protein pools by mu opioid, muscarinic cholinergic, and hypocretin/orexin receptor agonists. The potential health relatedness of these basic studies derives from the unwanted side effects of opioids on sleep and breathing.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057120-09
Application #
6748997
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (04))
Program Officer
Twery, Michael
Project Start
1997-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
9
Fiscal Year
2004
Total Cost
$357,653
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hambrecht-Wiedbusch, Viviane S; Gauthier, Elizabeth A; Baghdoyan, Helen A et al. (2010) Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation. Sleep 33:909-18
Watson, Christopher J; Baghdoyan, Helen A; Lydic, Ralph (2010) Neuropharmacology of Sleep and Wakefulness. Sleep Med Clin 5:513-528
Watson, Sarah L; Watson, Christopher J; Baghdoyan, Helen A et al. (2010) Thermal nociception is decreased by hypocretin-1 and an adenosine A1 receptor agonist microinjected into the pontine reticular formation of Sprague Dawley rat. J Pain 11:535-44
Van Dort, Christa J; Baghdoyan, Helen A; Lydic, Ralph (2009) Adenosine A(1) and A(2A) receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal. J Neurosci 29:871-81
Nelson, Ariana M; Battersby, Alanna S; Baghdoyan, Helen A et al. (2009) Opioid-induced decreases in rat brain adenosine levels are reversed by inhibiting adenosine deaminase. Anesthesiology 111:1327-33
Wang, Wenfei; Baghdoyan, Helen A; Lydic, Ralph (2009) Leptin replacement restores supraspinal cholinergic antinociception in leptin-deficient obese mice. J Pain 10:836-43
Brummett, Chad M; Padda, Amrita K; Amodeo, Francesco S et al. (2009) Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat. Anesthesiology 111:1111-9
Icaza, Eduardo E; Huang, Xinyan; Fu, Ying et al. (2009) Isoflurane-induced changes in righting response and breathing are modulated by RGS proteins. Anesth Analg 109:1500-5
Hambrecht, V S; Vlisides, P E; Row, B W et al. (2009) G proteins in rat prefrontal cortex (PFC) are differentially activated as a function of oxygen status and PFC region. J Chem Neuroanat 37:112-7
Vanini, Giancarlo; Watson, Christopher J; Lydic, Ralph et al. (2008) Gamma-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia. Anesthesiology 109:978-88

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