The long-term goal of the proposed research is to understand mechanisms by which chronic in utero morphine and methadone exposure affect regulation and function of mu opioid receptors (MOR) in respiratory control areas of newborn brainstem. Respiratory depression is induced by endogenous opioid peptides and exogenous opioids that activate MOR. A critical brainstem site for these effects is the nucleus tractus solitarius (NTS), which integrates sensory signals and drives respiratory muscles. Profound disturbance of neonatal breathing is a well-documented consequence of maternal opioid abuse. These neonates exhibit withdrawal hyperventilation and an increased incidence of sudden infant death syndrome (SIDS). The proposed studies are essential for understanding normal respiratory development, drug-induced changes, and effective treatment of pregnant heroin addicts and methadone maintained patients. The exact role of NTS MOR in neonatal congenital narcotic dependence and these respiratory disturbances is unknown. For anatomical, physiological, and pharmacological reasons, the guinea pig is a superb model for study of maternal opioid abuse. Guinea pig kappa opioid receptor has been cloned, but only partial sequences of MOR and delta opioid receptors have been available. However, our laboratory has recently determined the complete guinea pig MOR cDNA sequence. Availability of this sequence will enable us to define for the first time guinea pig MOR pharmacology, and systematically compare it to human and mouse MOR. Research is guided by four hypotheses: 1) guinea pig MOR is functionally similar to human MOR with respect to mu agonist efficacy, binding kinetics, and activation of G-protein, but different from murine MOR; 2) methadone induces respiratory depression and is equipotent to, but of longer duration than morphine in the neonatal guinea pig; 3) chronic in utero morphine and methadone exposure results in increased functional MOR on the cell surface, but decreases the coupling efficiency of MOR with G-proteins in the NTS; 4) chronic in utero morphine and methadone exposure up-regulates MOR mRNA in the NTS. Hypotheses are explored through four specific aims: 1) to compare mu agonist selectivity and potency, and development of cellular tolerance for guinea pig, human and murine MOR each expressed in stably transfected CHO cells; 2) to prove that the respiratory effects of methadone are similar to morphine in the neonatal guinea pig; 3) to study the effects of morphine and methadone on guinea pig MOR in NTS of brainstem sections from guinea pig neonates exposed in utero; and 4) to quantitate MOR mRNA in NTS from guinea pig neonates exposed to morphine and methadone in utero. These studies will provide developmental information on guinea pig NTS MOR following chronic in utero opioid exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007912-08
Application #
6730582
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Thadani, Pushpa
Project Start
1993-12-15
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
8
Fiscal Year
2004
Total Cost
$264,250
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Silverman, Daniel A N; Nettleton, Rosemary T; Spencer, Katherine B et al. (2009) S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig. Respir Physiol Neurobiol 169:252-61
Nettleton, Rosemary T; Wallisch, Michael; Olsen, George D (2008) Respiratory effects of chronic in utero methadone or morphine exposure in the neonatal guinea pig. Neurotoxicol Teratol 30:448-54
Wallisch, Michael; Nelson, Cole S; Mulvaney, Julia M et al. (2007) Effects of chronic opioid exposure on guinea pig mu opioid receptor in Chinese hamster ovary cells: comparison with human and rat receptor. Biochem Pharmacol 73:1818-28
Smith, Sue Ann; Stupfel, James T; Ilias, Nasreen A et al. (2004) Guinea pig mu opioid receptor: brainstem expression in the morphine-exposed neonate. Neurotoxicol Teratol 26:121-9
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Olsen, G D; Murphey, L J (1995) Effects of morphine and cocaine on breathing control in neonatal animals: a minireview. NIDA Res Monogr 158:22-39
Murphey, L J; Olsen, G D (1995) Developmental change of mu opioid receptors in neonatal guinea pig brain stem. Brain Res Dev Brain Res 85:146-8

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