Opioids comprise one of the most effective class of drugs for the clinical management of pain. Electroencephalographic data indicate that opioids significantly inhibit the rapid eye movement (REM) phase of sleep. This opioid-induced REM sleep inhibition has come to be understood as a major unwanted side effect of opioids. Furthermore, numerous studies have shown that when opioid therapy is discontinued there is a rebound increase in REM sleep that is associated with cardiopulmonary complications. Three lines of evidence emphasizes the health relatedness of opioid-induced REM sleep inhibition. First, since opioids are commonly used in the postoperative setting, a better understanding of opioid-induced cardiopulmonary complications is relevant for anesthesia and peri-operative medicine. Second. opioid therapy also is common for chronic pain management, and sleep disruption is the number one complaint of individuals suffering from chronic pain. Third, related to sleep disorders and pulmonary medicine is the fact that the periodic cessation of breathing (apnea) is most severe during REM phase of sleep cycle. the brain mechanisms causing opioid-induced REM sleep inhibition are poorly understood. The long-term goal of the four specific aims is to specify the cellular and molecular mechanisms through which opioids cause REM sleep inhibition. Brain stem cholinergic systems are known to play a major role in REM sleep generation, and the proposed experiments will study the effects of opioids on cholinergic neurotransmission.
Aim 1 will test the hypothesis that microinjection of opioid agonists into the cholinergic laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei will cause REM sleep inhibition and respiratory depression. Opioid receptors are linked to G proteins, and Aim 2 will test the hypothesis that in the medial pontine reticular formation (mPRF) the mu receptor/adenylyl cyclase/cAMP cascade modulates opioid-induced REM sleep inhibition.
Aim 3 will use microdialysis and HPLC to test the hypothesis that acetylcholine (ACh) levels in the mPRF are decreased by administering opioid agonists into the LDT/PPT. Inhibition of nitric oxide synthase (NOS) decreases ACh levels in the mPRF, and Aim 4 will test the hypothesis that mPRF administration of NOS inhibitors will potentiate the REM sleep inhibition and respiratory depression previously shown to be caused by mPRF opioids.
These aims are conceptually unified, and related to the long-term goal, by their ability to specify brain stem cholinergic neurons and mechanisms causally contributing to opioid-induced inhibition of REM sleep.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057120-05
Application #
6183786
Study Section
Psychobiology, Behavior, and Neuroscience Review Committee (PBN)
Project Start
1997-07-01
Project End
2001-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
5
Fiscal Year
2000
Total Cost
$186,918
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
791277940
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
Geisser, Michael E; Wang, Wenfei; Smuck, Matthew et al. (2008) Nociception before and after exercise in rats bred for high and low aerobic capacity. Neurosci Lett 443:37-40

Showing the most recent 10 out of 48 publications