The potent analgesic and psychological effects of opiates in animals have been recognized for centuries. The effects of both chronic and acute administration with opiates can occur in animals during their early life; therefore, prenatal exposure to opiates in addicted pregnant women has been a major social problem in this society. It is known that opioid receptors mediate the biological effects of both endogenous opioid peptides and administered opiates, and it is well documented that opiates have profound effects in many biological systems including early animal development. However, it is not known when and which opioid receptors begin to appear during developmental stages and what type of opioid receptors are responsible for the biological sequelae of opiates in animals. Recent cloning of several opioid receptors as well as the advancement in molecular biological techniques makes it possible to examine the molecular basis of the ontogenesis of opioid receptors and the mechanism of tolerance induction and withdrawal in utero as proposed here. Specifically, we will 1. determine the ontogenic profiles of mu, delta and kappa opioid receptors; 2. determine the effects of pharmacological and physiological (endocrine) agents on opioid receptor ontogenesis, as well as the association of opioid receptor gene expression with tolerance induction and development of withdrawal in prenatal stages. These studies will be conducted by first generating transgenic receptor mice carrying an beta-galactosidase (lacZ) or a green fluorescent protein (GFP) marker. Breeding of these transgenic mouse lines will generate double transgenic mice for parallel analysis for reporter gene expression on the same specimens, allowing the changing patterns of multiple opioid receptor genes to be examined simultaneously. This will provide unique information as to if and how the development of opioid receptor gene expression change their profile in the course of prenatal exposure to drugs or other agents. In addition, the molecular genetic basis for these changing profiles will be revealed.
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