Prenatal morphine exposure alters hippocampal opioids and seizures

Abstract

Maternal opiate abuse has adverse effects on human offspring and in rat models. Drugs administered during prenatal life may act on the systems that are developing at the time of drug exposure. Seizure susceptibility, which changes during development and as a result of alterations in gonadal hormone levels, was used to probe changes in the neuronal pathways that mediate neural excitation. The effect of prenatal morphine exposure (10 mg/kg twice daily on gestational days 11--18) on bicuculline seizure susceptibility was examined before, during, and after puberty, and as a function of gonadal hormone replacement after gonadectomy in adult male and female rats. Prenatal morphine exposure altered bicuculline seizure susceptibility in an age-, sex-, and gonadal hormone-dependent manner.;Because opioids play an important role in controlling seizure initiation and spread, the role of the endogenous opioid system in altered bicuculline seizure susceptibility in prenatally morphine-exposed adult males was assessed. Opioid receptors in prenatally morphine- and saline-exposed males were blocked with the non-specific opioid receptor antagonist naloxone before bicuculline seizure testing. Naloxone reversed the increased latency of prenatally morphine-exposed males.;Because endogenous opioids in the hippocampus play a major role in controlling seizure propagation, it was hypothesized that prenatally morphine-exposed male rats would have alterations in the hippocampal opioid system. To test this hypothesis, in situ hybridizations were utilized to measure proenkephalin and prodynorphin mRNA, and radioimmunoassays were used to quantify proenkephalin- and prodynorphin-derived peptide levels in the dentate gyrus (DG), CA3, and CA1 subfields of the hippocampus. In the DG, prenatal morphine exposure in male rats decreased proenkephalin mRNA and met-enkephalin peptide levels, and increased prodynorphin mRNA and dynorphin B peptide levels. In addition, receptor autoradiography demonstrated an increase in mu receptor labeling in discrete strata of specific hippocampal subfields, but no changes in delta receptor labeling. Together, the findings indicate that prenatal morphine exposure alters the hippocampal opioid system and bicuculline seizure susceptibility. Changes in the hippocampal opioid system could be involved in altered seizure propagation seen in prenatally morphine-exposed animals as well as other functional alterations mediated by the hippocampus, such as long term potentiation and learning and memory.