The goal of this proposal is to determine the extent and consequence of exposure of the guinea pig fetus and neonate to morphine-6-glucuronide (M6G), an active metabolite of morphine (MOR) and heroin. M6G will be quantitated in fetal and maternal tissues by high-performance liquidchrnmatography after chronic exposure to MOR. Maternal, fetal and neonatal production of M6G from MOR will be examined in hepatic microsomal preparations. The effect of chronic in utero MOR exposure upon neonatal breathing, oxygen consumption and carbon dioxide production will be studied using a noninvasive plethysmographic technique. Neonatal growth will be monitored. The interrelationship of dose, plasma and brain drug concentrations and intensity of respiratory depression will be examined in neonates as a function of age. Breathing effects of morphine-3-glucuronide (M3G), a metabolite of heroin and MOR with activities opposite to those of M6G, and the extent of its formation from MOR will be examined and compared to M6G. Ability of the opiate receptor antagonist naloxone to reverse the breathing depression of M6G will be compared to the hypothesized antagonistic effects of M3G. The guinea pig is an appropriate model for the human perinatal pharmacology of M6G in several respects: the guinea pig produces the glucuronide metabolites of MOR; the breathing response to narcotic drugs and carbon dioxide is similar in the two species; and the guinea pig has a hemomonochorial placenta similar in structure and permeability characteristics to the human placenta. The importance of M6G has only been recognized recently and therefore its fetal and neonatal pharmacology is virtually unknown. Since abuse of narcotic drugs, such as heroin and MOR, during pregnancy is a substantial public health problem in the United States, and in utero exposure to these drugs has been implicated in breathing abnormalities and in an increased incidence of the sudden-infant-death syndrome (SIDS), it is important to understand the pharmacology of active metabolites which may accumulate during pregnancy. The data from this research will be valuable in investigating whether active metabolites of heroin and MOR have a role in the development of neonatal breathing abnormalities some of which may contribute to SIDS, in educating women of child bearing age, and in caring for infants who have had in utero narcotic exposure.
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