Effects of single (20 mg/kg i.p.), and repeated morphine (increasing doses: from 20 to 100 mg/kg/day i.p., twice daily for 10 days) administration on the thyrotropin-releasing hormone (TRH) level and TRH receptors in discrete brain regions of the rat were investigated. As shown by a specific radioimmunoassay, a single dose of morphine increased the TRH level in the septum only. At 2 h after the last dose of repeated morphine, no significant changes in the TRH level were observed. At 72 h after the last morphine injection, the TRH level was increased in the striatum and hippocampus, but remained unchanged in the nucleus accumbens and septum. A radioreceptor assay showed that acute morphine had no effect on the density or affinity of TRH receptors in the brain regions studied. In contrast, repeated morphine increased the Kd of TRH receptors in the striatum at 2 h (by ca 42%) and 72 h (by ca 26%), and in the nucleus accumbens at 72 h (by ca 26%) after the last drug injection. At 2 h after the last morphine injection, the Bmax of TRH receptors was decreased in the nucleus accumbens (by ca 41%) and unchanged in other structures, whereas at 72 h it was elevated by ca 27% and 49% in the striatum and hippocampus, respectively. The above results indicate that repeated but not acute administration of morphine leads to long-lasting, region-specific changes in both the TRH level and receptors.