Prenatal Opiate Withdrawal Activates the Chick Embryo Hypothalamic-Pituitary-Adrenal Axis and Dilates Vitelline Blood Vessels via Serotonin2 Receptors
- 1Department of Pharmacology (L.M.S., M.I.B., X.Z., S.B.S.) and2Graduate Program in Neuroscience (S.B.S.), University of Minnesota, Minneapolis, Minnesota
- Dr. Lisa M. Schrott, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455. E-mail: schro041{at}umn.edu
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 opiateN-desmethyl-l-α-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.
Footnotes
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↵1 Current Address: Center for Alternative Medicine and Addiction Research, Minneapolis Medical Research Foundation, 914 S 8th St. D-3, Minneapolis, MN 55404.
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This work was supported, in part, by U.S. Public Health Service Grants K01 DA00362 (to L.M.S.), R37 DA04979 (to S.B.S.), and T32 DA07097 (for support of M.I.B.). Portions of this work have previously been presented at the following meetings: Schrott LM, Larson EB, Stanek JA, and Sparber SB (2000) Serum corticosterone as a marker for both prenatal naloxone-induced and postnatal spontaneous opiate withdrawal in the chicken. Society for Neuroscience, Miami, FL.; and Zhang X and Sparber SB (2000) Ritanserin blocks extraembryonic vasodilation caused by opiate withdrawal in chicken embryos. College on Problems of Drug Dependence, San Juan, Puerto Rico.
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DOI: 10.1124/jpet.102.037044
- Abbreviations:
- HPA
- hypothalamic-pituitary-adrenal
- NLAAM
- N-desmethyl-l-α-noracetylmethadol
- Nx
- naloxone
- E. embryonic day
- IBMX, isobutylmethylxanthine
- 5-HT
- 5-hydroxytryptamine (serotonin)
- ANOVA
- analysis of variance
- PLSD
- protected least significant difference
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- Received April 4, 2002.
- Accepted June 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
