Prenatal opiate withdrawal activates the chick embryo hypothalamic pituitary-adrenal axis and dilates vitelline blood vessels via serotonin(2) receptors

J Pharmacol Exp Ther. 2002 Oct;303(1):257-64. doi: 10.1124/jpet.102.037044.

Abstract

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-alpha-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 serotonin(2) (5-HT(2)) receptors were involved in other withdrawal manifestations, so we determined whether they were likewise involved. Pretreatment with the 5-HT(2) antagonist ritanserin completely blocked HPA axis activation and vasodilation associated with both Nx-precipitated withdrawal and IBMX administration. This indicates that 5-HT(2) receptors, directly or indirectly, mediate these withdrawal manifestations in the chick embryo.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Chick Embryo
  • Corticosterone / blood*
  • Disease Models, Animal
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiology*
  • Methadyl Acetate / analogs & derivatives*
  • Methadyl Acetate / toxicity
  • Morphogenesis
  • Naloxone / antagonists & inhibitors
  • Naloxone / toxicity*
  • Narcotics / toxicity*
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiology*
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Ritanserin / pharmacology*
  • Substance Withdrawal Syndrome

Substances

  • Narcotics
  • Receptors, Serotonin
  • Ritanserin
  • paracymethadol
  • Naloxone
  • Methadyl Acetate
  • 1-Methyl-3-isobutylxanthine
  • Corticosterone