Vol. 303, Issue 1, 257-264, October 2002

Prenatal Opiate Withdrawal Activates the Chick Embryo Hypothalamic-Pituitary-Adrenal Axis and Dilates Vitelline Blood Vessels via Serotonin₂ Receptors

Lisa M. Schrott, Mary Irene Baumgart, Xuewei Zhang¹ and Sheldon B. Sparber

Department of Pharmacology (L.M.S., M.I.B., X.Z., S.B.S.) and Graduate Program in Neuroscience (S.B.S.), University of Minnesota, Minneapolis, Minnesota

Opiate withdrawal during pregnancy may occur because of voluntary or forced detoxification, or from rapid cycling associated with exposure to short-acting "street" opiates. Thus, animal modeling of prenatal withdrawal and development of potential therapeutic interventions is important. Direct developmental effects of opiates and/or withdrawal can be studied using a chick model. In ovo administration of the long-acting opiate N-desmethyl-l--noracetylmethadol (NLAAM) induces opiate dependence in the chick embryo. We examined activation of the hypothalamic-pituitary-adrenal (HPA) axis (assessed via serum corticosterone) and hemodynamic changes (assessed as changes in apparent diameter of vitelline (extraembryonic) blood vessels) after chronic NLAAM exposure and naloxone (Nx)-precipitated withdrawal during late stages of embryogenesis. Nx-precipitated withdrawal increased corticosterone 2- to 4.5-fold and diameters of vitelline blood vessels by 15 to 45%. NLAAM exposure itself did not effect these measures. In a second set of experiments, isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, was injected into eggs with embryos. IBMX similarly increased corticosterone and vitelline vessel diameter, with a similar time course and response magnitude. Previous studies found that serotonin₂ (5-HT₂) receptors were involved in other withdrawal manifestations, so we determined whether they were likewise involved. Pretreatment with the 5-HT₂ antagonist ritanserin completely blocked HPA axis activation and vasodilation associated with both Nx-precipitated withdrawal and IBMX administration. This indicates that 5-HT₂ receptors, directly or indirectly, mediate these withdrawal manifestations in the chick embryo.