The effect of opioid promoting social behavior is negatively regulated by the activity of dorsomedial part of periaqueductal grey

The opioid system has been reported to play a crucial role in modulating social behavior in humans and animals. However, brain regions which mediate the effect of opioids on promoting sociability and reason why the effect is suppressed depending on the dose are not determined yet. Opioid receptors are densely distributed in mPFC and NAc, which could promote sociability. On the other hand, PAG, a key region for analgesia of opioids, is reported to negatively affect sociability. Thus we hypothesized that sociability would be promoted by controlling these regions in a well-balanced manner. Firstly, we confirmed that morphine (Mor, s.c.) with a low dose increased social interaction behavior in mice. At that dose, the number of c-Fos-positive cells was significantly increased in mPFC and NAc. At a higher dose, dorsomedial (dm), but not dorsolateral/lateral, PAG was activated in addition to mPFC and NAc. At last, we found that the effect on social behavior induced by Mor (low dose, s.c.) was antagonized by topical administration of high dose Mor to dmPAG. These results suggest that the dmPAG works as a gate of social behavior promoted by Mor-induced activation of mPFC and NAc. A new opioid drug with an appropriate action that does not activate dmPAG may be a new therapeutic strategy for the deficit of sociability in mental disorders.