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The same chemicals and receptors that control the sensation of pain in the opioid system also play a role in regulating social behavior. The body produces natural opioid substances which are drawn to receptors throughout the nervous system, sending signals through neurons that induce pain relief, pleasure, and more. Low-dose morphine and buprenorphine that attach to the mu (¦Ì) opioid receptors (MORs) could help promote social interactions, which could help people with neuropsychiatric disorders such as autism spectrum disorder (ASD) that affect social interactions.

Results showing the impact of morphine and buprenorphine, two MOR agonists, on social behaviors in mice were published in on 6 December. 

¡°The opioid system plays a crucial role in modulating social behavior as well as pain sensation in both humans and animals. However, the pharmacological profile on social behavior and their therapeutic potential in ASD remain unclear. Our study presents novel evidence that low-dose opioids without analgesic and addictive effects can address social behavior deficits in ASD model mice,¡± said , a professor at Â鶹AV¡¯s Graduate School of Biomedical and Health Sciences in Hiroshima, Japan. 

To test the theory that opioids could help improve social behavior, researchers studied different doses of the MOR agonist drugs morphine and buprenorphine. The doses were tested on normal, or na?ve, mice, and mice that had been exposed to valproic acid (VPA) before they were born. VPA-exposed mice are a common animal model of ASD. After receiving a dose of either morphine or buprenorphine, the mouse was then put into a small chamber with an unfamiliar mouse. When the mice did not want to interact with and moved away from the unfamiliar mouse, they were in the avoidance zone. When the mice interacted, they were in the interaction zone.

For na?ve mice and for VPA-exposed mice, low-dose morphine (0.03 mg/kg) increased the amount of time spent in the interaction zone. When the dose of morphine was increased to 5 mg/kg, time spent in the interaction zone decreased. For the VPA-exposed mice, low-doses of morphine of 0.03 and 0.1 mg/kg improved social deficits, but higher doses of 0.3, 1, or 3 mg/kg did not. This means that the low-dose morphine increased the social interactions of all the mice, not just the VPA-exposed mice. 

After the tests, researchers took brain scans of the mice. At the 0.03 mg/kg dose, there was evidence in the brain that the morphine was affecting neuronal activity, but it did not affect the ventral tegmental area (VTA). The VTA is a part of the brain that is associated with addiction behaviors from opioids through mediating dopamine release in downstream regions. In comparison, at the 5 mg/kg dose, the VTA was impacted. This suggests that the low-dose morphine would not be as addictive as higher doses. Scans were also taken of the dorsal periaqueductal gray (PAG), a region of the brain that is associated with opioid pain relief and fear-like behaviors. When this part of the brain is activated, social interactions are suppressed and anxiety, avoidance, and defensiveness all increase. At the lower dose (0.03 mg/kg), this region was not impacted, but it was at the 5 mg/kg dose.

¡°Opioids have serious side effects, such as addiction and respiratory depression, and must be used with caution. It is also true that endogenous opioids exist in mammals, including humans, and their signaling plays an important role in pain perception, defense, and social behavior, and thus low-dose opioids may have other medical benefits beyond analgesia as ketamine has,¡± said Ago. ¡°Our findings indicate, for the first time, the therapeutic potential of non-addictive low-dose opioids for ASD and highlight the activation of dorsomedial periaqueductal gray as a key determinant of the dose-specific effects of opioids on social behavior.¡±

Initial clinical trial underway

Future research will need to be done to ensure the low-dose morphine is not as addictive as higher doses. One alternative may be low-dose buprenorphine, which is a class III drug and showed similar results during this study as low-dose morphine and lasted longer than the low-dose morphine. 

Because human and rodent opioid systems are so similar and the results of this study were promising, an initial clinical trial with a human participant is already underway. ¡°In the future, we aim to develop a new treatment strategy for ASD through further investigation in animal models and testing in humans,¡± said Ago.

Other contributors include Soichiro Ohnami, Keiko Takasu, Yuki Azuma, Koichi Ogawa, Atsushi Nakamura, and Hidekuni Yamakawa at Shionogi & Co. Ltd.; Megumi Naito, Haruki Kawase, Momoko Higuchi, Shigeru Hasebe, Rei Yokoyama, Kazuhiro Takuma, and Hitoshi Hashimoto at Osaka University; Ryo Kanemaru at Shionogi TechnoAdvance Research Co. Ltd.; and Takahiro Kochi, Takeru Tahara, and at Â鶹AV.

The Japan Society for the Promotion of Science KAKENHI, the Nakatomi Foundation, the Astellas Foundation for Research on Metabolic Disorders, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Research Support Project for Life Science and Drug Discovery from Japan Agency for Medical Research and Development supported this research. 

Journal: JCI Insight
Title: Brain region¨Cspecific neural activation by low-dose opioid promotes social behavior
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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