Brain region–specific neural activation by low-dose opioid promotes social behavior
Soichiro Ohnami, Megumi Naito, Haruki Kawase, Momoko Higuchi, Shigeru Hasebe, Keiko Takasu, Ryo Kanemaru, Yuki Azuma, Rei Yokoyama, Takahiro Kochi, Eiji Imado, Takeru Tahara, Yaichiro Kotake, Satoshi Asano, Naoya Oishi, Kazuhiro Takuma, Hitoshi Hashimoto, Koichi Ogawa, Atsushi Nakamura, Hidekuni Yamakawa, Yukio Ago
Soichiro Ohnami, Megumi Naito, Haruki Kawase, Momoko Higuchi, Shigeru Hasebe, Keiko Takasu, Ryo Kanemaru, Yuki Azuma, Rei Yokoyama, Takahiro Kochi, Eiji Imado, Takeru Tahara, Yaichiro Kotake, Satoshi Asano, Naoya Oishi, Kazuhiro Takuma, Hitoshi Hashimoto, Koichi Ogawa, Atsushi Nakamura, Hidekuni Yamakawa, Yukio Ago
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Research Article Neuroscience Therapeutics

Brain region–specific neural activation by low-dose opioid promotes social behavior

Abstract

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.

Authors

Soichiro Ohnami, Megumi Naito, Haruki Kawase, Momoko Higuchi, Shigeru Hasebe, Keiko Takasu, Ryo Kanemaru, Yuki Azuma, Rei Yokoyama, Takahiro Kochi, Eiji Imado, Takeru Tahara, Yaichiro Kotake, Satoshi Asano, Naoya Oishi, Kazuhiro Takuma, Hitoshi Hashimoto, Koichi Ogawa, Atsushi Nakamura, Hidekuni Yamakawa, Yukio Ago

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Figure 1

Morphine increased social behaviors in mice only at low doses.

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Morphine increased social behaviors in mice only at low doses. (A–D) Eff...
(A–D) Effects of systemic administration of morphine on social behaviors in the single-chamber social interaction test (SIT). Single-housed C57BL/6J mice were s.c. injected with morphine (0.03 or 5 mg/kg) or vehicle at 12–13 weeks of age. The time spent in the interaction zone (A and C) and the avoidance zone (B and D) during a 3-minute test period with an unfamiliar mouse kept in a cage (target session) is shown. n = 21–22 (A and B) and 11 animals (C and D). (E) Effects of systemic administration of morphine on social interaction deficits in mice prenatally exposed to valproic acid (VPA) in the reciprocal SIT. VPA (500 mg/kg) or saline was intraperitoneally injected into pregnant CD-1 mice at embryonic day 12.5. Male offspring at 8 weeks of age were s.c. injected with morphine (0.03, 0.1, 0.3, 1, 3 mg/kg) or vehicle, and the duration of sniffing was measured during a 20-minute test period. n = 5–13 animals. (F) Effects of morphine on thermal nociception in prenatally VPA-treated mice. The withdrawal latency at 49°C was measured with the hot-plate test at 1 hour after administration of morphine (0.1, 1 mg/kg, s.c.). n = 12 animals. Data are shown as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, by the parametric tests (A, D, and E) or nonparametric ones (B, C, and F) compared with vehicle-treated mice. ##P < 0.01 compared with mice prenatally exposed to saline (control). Mor, morphine.