Time course of morphine withdrawal and preproenkephalin gene expression in the periaqueductal gray of rats.
We have previously reported the increase of preproenkephalin (PPE) mRNA in the caudal periaqueductal gray (PAG) of rats during morphine withdrawal. In this study, it was further evidenced that PPE mRNA in the caudal PAG was not increased by various kinds of stressor, suggesting that the increase in PPE mRNA in the caudal PAG is specific to morphine withdrawal. In order to investigate the physiological significance of the increase of PPE mRNA in the caudal PAG, we compared the time course of the increase of PPE mRNA in the caudal PAG with that of naloxone-precipitated or spontaneous morphine withdrawal signs. The increase of plasma corticosterone (PCS: 52 and 52 microg/100 ml; control group, 18 and 15 microg/100 ml) and body weight loss (-6 and -9%; control group, 0 and -1%) were observed but PPE mRNA increase was not detected 1 and 2 h after naloxone in morphine treated rats. PPE mRNA increased by 37 to 56%, while PCS elevation and body weight loss gradually diminished 4 h to 2 days after naloxone. A total of 12 h after spontaneous withdrawal, PCS was prominently increased (51 microg/100 ml; control group, 12 microg/100 ml), but body weight and PPE mRNA were not affected. One day after spontaneous withdrawal, PCS elevation (38 microg/100 ml; control group, 8 microg/100 ml) and body weight loss (-5%; control group, +3%) were observed and PPE mRNA also increased by 42%. Two to 3 days after the final morphine injection, PCS recovered to control level and body weight loss gradually disappeared, while PPE mRNA was still increased by 74 to 46%. These results suggest that PPE gene expression in the caudal PAG is stimulated in the recuperative phase of these morphine withdrawal signs.