Gene-peptide relationships in the developing rat brain: the response of preproenkephalin rnRNA and [Met5]-enkephalin to acute opioid antagonist (naltrexone) exposure

Abstract

[Met5]-enkephalin, encoded by the preproenkephalin (PPE) gene, serves as a growth factor during brain development in addition to its role as a neurotransmitter. This study examined the relationship of gene and peptide expression in the developing (postnatal day 6) rat brain by disrupting peptide-receptor interaction with either a brief (4-6 h) or continuous opioid receptor blockade using a single injection of 1 or 50 mg/kg naltrexone (NTX), respectively; such perturbations result in growth inhibition or acceleration, respectively. In the caudate putamen, an area that has completed neurogenesis by postnatal day 6 and has an abundance of PPE mRNA and enkephalins in adulthood, NTX did not influence PPE mRNA in either NTX group, or the enkephalin levels in the 1 mg/kg NTX group. [Met5]-enkephalin values in the neostriatum, however, were 67-183% greater than controls in rats given 50 mg/kg NTX, beginning 5 min after drug injection. In the cerebellum, PPE mRNA expression was depressed from 5 min to 4 h in the 1 mg/kg NTX group, and was normal thereafter; mRNA levels in the 50 mg/kg NTX group were markedly subnormal for 24 h. Enkephalin levels were significantly depressed within 5 min of drug injection and remained so for 4 h in the 1 mg/kg NTX group, but were elevated to approximately 135% of control values at 8, 16, and 24 h. Enkephalin levels were not changed in the cerebellum of the 50 mg/kg NTX group, or in the plasma of either NTX group. These data suggest that a single exposure to NTX can affect transcriptional and translational mechanisms related to PPE mRNA and opioid peptide expression in a rapid and sustained manner, and that this treatment elicits a specific pattern of alterations dependent upon the brain region sampled, drug dosage, and/or the duration of opioid receptor blockade. Additionally, our results indicate that the decreased DNA synthesis in external germinal cells occurring after opioid receptor blockade as recorded earlier may be related to an increase in the potent opioid growth factor, [Met5]-enkephalin.