Brain Region-specific Neural Activation by Low-dose Opioid Promotes Social Behavior

The opioid system plays crucial roles in modulating social behaviors in both humans and animals. However, the pharmacological profiles of opioids regarding social behavior and their therapeutic potential remain unclear. Multiple pharmacological, behavioral, and immunohistological c-Fos mapping approaches were used to characterize the effects of μ-opioid receptor agonists on social behavior and investigate the mechanisms in naive mice and autism spectrum disorder-like (ASD-like) mouse models, such as prenatally valproic acid-treated mice and Fmr1-KO mice. Here, we report that low-dose morphine, a μ-opioid receptor agonist, promoted social behavior by selectively activating neurons in prosocial brain regions, including the nucleus accumbens, but not those in the dorsomedial periaqueductal gray (dmPAG), which are only activated by analgesic high-dose morphine. Critically, intra-dmPAG morphine injection counteracted the prosocial effect of low-dose morphine, suggesting that dmPAG neural activation suppresses social behavior. Moreover, buprenorphine, a μ-opioid receptor partial agonist with less abuse liability and a well-established safety profile, ameliorated social behavior deficits in two mouse models recapitulating ASD symptoms by selectively activating prosocial brain regions without dmPAG neural activation. Our findings highlight the therapeutic potential of brain region-specific neural activation induced by low-dose opioids for social behavior deficits in ASD.