Brain opioid receptor adaptation and expression after prenatal exposure to buprenorphine.
Previous in vivo studies revealed that buprenorphine can down-regulate mu and up-regulate delta2 and kappa1 opioid receptors in adult and neonatal rat brain. To assess gestational effects of buprenorphine on offspring, pregnant rats were also administered this drug and opioid receptor binding parameters (Kd and Bmax values) were measured by homologous binding assays of postnatal day 1 (P1) brain membranes. Buprenorphine concentrations of 2.5 mg/kg injected into dams elicited an up-regulation of kappa1 opioid receptors as detected with the kappa1-selective agonist 3H-U69593. Parallel studies with the mu-selective agonist [D-ala2, mephe4,gly-ol5] enkephalin revealed a buprenorphine-induced down-regulation in receptor density at 0.3, 0.6 or 2.5 mg/kg drug treatment. A greater down-regulation of mu receptors for P1 males than for their female counterparts was observed. Buprenorphine did not cause a reduction in binding affinity in these experiments. Changes in opioid receptor adaptation induced by buprenorphine were further supported by data from cross-linking of 125I-beta-endorphin to brain membrane preparations. RT-PCR analysis of opioid receptor expression was also estimated in P1 brains. However, significant changes in neither mu nor kappa receptor message were detected in P1 brains as a result of prenatal buprenorphine treatment under the conditions of these experiments. Since buprenorphine is being evaluated in clinical trials for the treatment of heroin abuse, the in utero actions of the drug have ramifications for its use in the treatment of maternal drug abuse.
Belcheva
M M
MM
Departments of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
Bohn
L M
LM
Ho
M T
MT
Johnson
F E
FE
Yanai
J
J
Barron
S
S
Coscia
C J
CJ
D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002047:Buprenorphine / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D005260:Female; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001615:beta-Endorphin / Q000187:drug effects / Q000378:metabolism
D003432:Cross-Linking Reagents; D004745:Enkephalins; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002047:Buprenorphine; D001615:beta-Endorphin