The overall goal of this research is to examine the development of mu opioid receptors in the brainstem of the neonatal guinea pig in order to better understand the respiratory effects of chronic in utero morphine exposure and the role of morphine's active metabolite, morphine-6-beta-D-glucuronide (M6G), in respiratory depression. There are three main aspects to this proposal on the study of the mu opioid receptor that, when combined, make it unique. They are: 1) location, with the emphasis on the respiratory nuclei of the brainstem; 2) development, with the emphasis on the neonatal animal during the first week after birth; and 3) treatment, with the emphasis on chronic intermittent versus a constant rate of in utero morphine exposure. The anatomical studies include the localization and quantitation of mu opioid receptors and receptor mRNA using immunohistochemistry, autoradiography, in situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR); the pharmacological studies include characterization of binding profiles of brainstem membranes and stably transfected CHO cells; and the functional studies include the determination of opioid-induced GTPgammaS binding in tissue and cells. These studies will provide new information about the role of mu receptors in development, morphine-induced respiratory depression, and importantly, the relationship of M6G binding (to mu and to a potential atypical site) in morphine-induced respiratory effects. The hypotheses are: 1) that there are developmental changes in D- Ala2-MePhe4-Gly-ol5-enkephalin (DAMGO) binding and opioid-induced GTPgammaS binding in brainstem respiratory nuclei during the first week of life; 2) that developmental changes in the mu opioid receptor are affected by in utero morphine exposure; and 3) that there are quantitative and qualitative differences between [3H]-DAMGO and [3H]-M6G binding and opioid-induced GTPgammaS binding in the brainstem during postnatal development and following in utero morphine exposure. Changes in opioid receptors associated with respiratory nuclei have consequences for the effects of morphine and M6G on breathing. This study is of significance for the fetus and neonate who are exposed in utero to heroin or other opioids because of maternal drug abuse, maintenance therapy of pregnant former opioid abusers or pain therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007912-06
Application #
6342255
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Thadani, Pushpa
Project Start
1993-12-15
Project End
2002-12-31
Budget Start
2001-01-01
Budget End
2002-12-31
Support Year
6
Fiscal Year
2001
Total Cost
$167,004
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Wallisch, Michael; Subban, Chinmayee V; Nettleton, Rosemary T et al. (2010) Chronic in utero buprenorphine exposure causes prolonged respiratory effects in the guinea pig neonate. Neurotoxicol Teratol 32:398-405
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
Matsuda, A Y; Olsen, G D (2001) Chronic in utero morphine exposure alters mu-agonist-stimulated [35S]-GTPgammaS binding in neonatal and juvenile guinea pig brainstem regions associated with breathing control. Neurotoxicol Teratol 23:413-9
Gray, R E; Munks, M W; Haynes, R R et al. (2001) Mu opioid receptor efficacy and potency of morphine-6-glucuronide in neonatal guinea pig brainstem membranes: comparison with transfected CHO cells. Brain Res Bull 54:499-505
Hunter, M A; Vangelisti, G R; Olsen, G D (1997) Chronic intermittent in utero exposure to morphine: effects on respiratory control in the neonatal guinea pig. Biol Neonate 72:293-304
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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