The effects of opioid (e.g., morphine) withdrawal on levels of endogenous opioid peptides and their mRNA in the various brain regions have been studied. However, the role of this opioidergic mechanism in the mediation of opioid withdrawal is not fully understood. Preproenkephalin (PPE) mRNA in the caudal periaqueductal gray (cPAG), an important brain region in opioid withdrawal, is increased by both opioid antagonist (naloxone)-precipitated and spontaneous morphine withdrawal, but not by various other stresses in rats, indicating a role of endogenous enkephalins in the cPAG in morphine withdrawal. In addition, PPE mRNA levels in the cPAG increase in the course of the dissipation of morphine withdrawal, and they are returned to the control levels after disappearance of morphine withdrawal signs. Local administration of an enkephalin analog or peptidase inhibitors into the cPAG suppresses morphine withdrawal signs. These facts suggest that enkephalinergic neurons in the PAG may have a critical role in the recovery phase of morphine withdrawal. Recently, an involvement of transcription factors in morphine withdrawal has been suggested. Thus, the possible role of transcription factors in the regulation of PPE gene expression in the cPAG during morphine withdrawal is also discussed.