Chronic pain induced by social defeat stress: a possible mechanism underlying free fatty acid-GPR40/FFAR1 in the brain

[Speaker] Fuka Aizawa:1
[Co-author] Takuya Yamashita:2, Kazuo Nakamoto:1, Fumiyo Kasuya:2, Shogo Tokuyama:1
1:Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan, 2:Biochemical Toxicology Laboratory, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan

Background; Emotional dysfunction such as depression or anxiety can cause the development of chronic pain and, conversely, chronic pain can induce emotional dysfunction. A decrease in the amount of fatty acids (FAs) in the brain has been suggested to be related to the development of emotional dysfunction and pain. GPR40/FFAR1, one of the G-protein coupled receptor, is activated by middle to long chain free fatty acids including docosahexaenoic acids (DHA). We have already reported brain GPR40/FFAR1 closely relate the regulation both pain and emotion. In the present study, we tested the involvement of GPR40/FFAR1 signaling in the brain during social defeat (SD) stress-induced pain prolongation.
Methods; C57BL/6J mice (9 weeks old) were subjected to SD stress for 10 consecutive days. Postsurgical pain was induced by a plantar incision in the right hind paw of mice after completed SD stress. The changes of fatty acids in the brain of mice subjected to 1 or 10 days SD stress were analyzed by LC-MS/MS. Continuous administration of GW1100 (1.0 µg/12 µL/day/mouse, 0.5 µL/h), a GPR40/FFAR1 antagonist was performed by osmotic infusion pump for 14 days underlying SD stress phase. Mechanical hypersensitivity was evaluated by a von Frey filament test. Withdrawal response following hind paw stimulation was measured 10 times.
Results; In one-day SD-stressed mice, the level of DHA, arachidonic acid (AA) and linoleic acid (LA) increased in the prefrontal cortex (PFC). Furthermore, in ten-day SD-stressed mice, the increase of DHA, AA, LA, stearic acid, and oleic acid were more increased in the PFC and the hypothalamus than that of one day SD stressed mice. Chronically SD-stressed mice showed continuous induction of mechanical allodynia until 21 days after paw surgery compared to just 4 days in control mice. This mechanical allodynia was markedly prolonged by continuous infusion of the GPR40/FFAR1 antagonist, GW1100, into the brain by osmotic mini-pump during chronic SD stress.
Conclusion; Our findings indicate that fatty acid-GPR40/FFAR1 signaling might be important factor to regulate the pain prolongation induced after received emotional dysfunction.
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