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 4

Low-dose buprenorphine increased social behaviors in VPA-treated and Fmr1-KO mice.

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Low-dose buprenorphine increased social behaviors in VPA-treated and Fmr...
(A) Effects of systemic buprenorphine administration on social behavior deficits in mice prenatally exposed to valproic acid (VPA) in the reciprocal social interaction test. Buprenorphine (1, 3, 10, or 30 μg/kg) or vehicle was s.c. injected into male offspring at 8 weeks of age. One hour after administration, the sniffing duration was measured during a 20-minute test period. (B) Effects of buprenorphine on thermal nociception in VPA-treated mice. The withdrawal latency at 49°C was measured with a hot-plate test 1 hour after buprenorphine administration (3 or 30 μg/kg, s.c.). (C and D) Effects of buprenorphine (3 or 30 μg/kg, s.c.) on social interaction deficits in VPA-treated mice were examined at 3 (C) or 12 hours (D) after administration. (E) The effects of buprenorphine (3 μg/kg, s.c.) on social interaction deficits were antagonized by naloxone (1 mg/kg, s.c.), an MOR antagonist, in VPA-treated mice. (F) Effects of systemic buprenorphine administration (3 μg/kg, s.c.) on disrupted social preference in Fmr1-KO mice. The time spent in the zone with or without an unfamiliar mouse was measured during a 10-minute test period. n = 11–18 animals. Data are shown as the mean ± SEM. ##P < 0.01, by parametric test (A) or nonparametric one (F) compared with vehicle-treated control mice prenatally exposed to saline (A) or vehicle-treated wild-type (C57BL/6J) mice (F). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by parametric tests (A–C) or nonparametric ones (D–F) compared with vehicle-treated mice prenatally exposed to VPA (A–E) or vehicle-treated Fmr1-KO mice (F). Bup, buprenorphine; MOR, μ-opioid receptor; Fmr1, fragile X mental retardation 1.