Previously, we have developed an early life stress model mice which subjected to maternal separation combined with social isolation (MSSI). These mice showed emotional dysfunction associated with early life stress, and exacerbated nerve injury-induced mechanical allodynia. In this study, to elucidate the mechanism underlying early life stress-induced increase of pain sensitivity, we investigated the changes of each opioid receptors mRNA expression in an each brain area of MSSI mice. Furthermore, we tested the changes of c-Fos induction in each brain area of MSSI mice after morphine injection by using immunohistochemical study. In the periaqueductal gray (PAG) area,a region that is implicated in the opioid control of nociception, m-, d-andk-opioid receptor (MOR, DOR and KOR) mRNAexpression were significantly decreased in MSSI model mice compared to control mice. A large number of c-Fos positive cells were observed in the PAG are of Control mice with morphine injection. On the other hand, in the PAG of MSSI model mice, c-Fos positive cells are hardly detectable after morphine injection. Finally, we conclude that MSSI induced decrease of MORmRNA expression and neuronal activity in the PAG area, suggesting that this phenomenon could be induced the increase of pain sensitivity in MSSI model mice.