Belcheva M M, Bohn L M, Ho M T, Johnson F E, Yanai J, Barron S, Coscia C J
Departments of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
Brain Res Dev Brain Res. 1998 Nov 1;111(1):35-42. doi: 10.1016/s0165-3806(98)00117-5.
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.
先前的体内研究表明，丁丙诺啡可下调成年和新生大鼠脑中的μ阿片受体，并上调δ2和κ1阿片受体。为了评估丁丙诺啡对后代的妊娠影响，对怀孕大鼠也给予了这种药物，并通过出生后第1天（P1）脑膜的同源结合试验测量了阿片受体结合参数（Kd和Bmax值）。向母鼠注射2.5mg/kg的丁丙诺啡浓度，用κ1选择性激动剂3H-U69593检测到κ1阿片受体上调。用μ选择性激动剂[D-ala2，mephe4，gly-ol5]脑啡肽进行的平行研究表明，在0.3、0.6或2.5mg/kg药物处理下，丁丙诺啡可诱导受体密度下调。观察到P1雄性大鼠的μ受体下调程度大于雌性大鼠。在这些实验中，丁丙诺啡没有导致结合亲和力降低。125I-β-内啡肽与脑膜制剂交联的数据进一步支持了丁丙诺啡诱导的阿片受体适应性变化。还对P1脑进行了阿片受体表达的RT-PCR分析。然而，在这些实验条件下，产前丁丙诺啡治疗并未在P1脑中检测到μ受体或κ受体信息的显著变化。由于丁丙诺啡正在进行治疗海洛因成瘾的临床试验评估，该药物在子宫内的作用对其用于治疗母体药物成瘾具有影响。
