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.
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