Brain opioid receptor adaptation and expression after prenatal exposure to buprenorphine

Previous in vivo studies revealed that buprenorphine can down-regulate μ and up-regulate δ₂ and κ₁ 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 (K(d) and B(max) 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 κ₁ opioid receptors as detected with the κ₁-selective agonist ³H-U69593. Parallel studies with the μ-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 μ 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-β-endorphin to brain membrane preparations. RT-PCR analysis of opioid receptor expression was also estimated in P1 brains. However, significant changes in neither μ nor κ 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.