PT640. The dysfunction of brain free fatty acid receptor GPR40/FFAR1 signaling relate to the development of chronic pain

Objective: It was previously reported that increasing serum level of glucagon-like peptide-2 (GLP-2) is a risk factor of migraine in human. The headache phase of a migraine attack is thought to originate in vasodilation of meningeal blood vessels followed by activation of the nociceptive trigeminal nerve innervating these vessels. However, it is unclear how GLP-2 acts on this pathway. In the present study, we investigated the effects of GLP-2 on the diameter of meningeal blood vessels, and determined the target cells of GLP-2 in the meningeal tissue. Methods: Meningeal preparations were isolated from male ddY mice (5–6 weeks). GLP-2 (10–100 nM) was perfused, and the meningeal arteriolar diameter was measured using infrared-differential interference contrast microscopy. The nitric oxide synthase (NOS) inhibitor, L-nitro-arginine-methyl-ester (L-NAME), was co-perfused with GLP-2. Mice were fixed by cardiac perfusion of 4% paraformaldehyde, and GLP-2 receptors were detected with immunofluorescence staining in the meningeal tissue. Results: GLP-2 (100 nM) dilated the meningeal blood vessels, which was prevented by the co-treatment with L-NAME. In the immunofluorescence staining, GLP-2 receptor-like immunoreactivites were detected in the macrophage marker Iba-1 positive cells, but not in the meningeal artery and isolectin B4, a marker of nociceptive C-fiber, positive neurons. Conclusion: GLP-2 dilates the meningeal blood vessels via macrophage NOS-independent mechanisms. This supports a crucial role of GLP-2 in the development of migraine. Policy of full disclosure: None. PT640 The dysfunction of brain free fatty acid receptor GPR40/FFAR1 signaling relate to the development of chronic pain Kazuo Nakamoto1, Fuka Aizawa1, Akira Hirasawa2, Fumiyo Kasuya1, Yutaka Koyama3, Takashi Kurihara4, Mitsumasa Mankura5, Atsuro Miyata4, Takashi Nishinaka1, Shogo Tokuyama1, Takuya Yamashita1 1Kobe Gakuin University, Japan, Kyoto University, Japan, 3Osaka Ohtani University, Japan, 4Kagoshima University, Japan, 5Kurashiki Sakuyo University, Japan Abstract Previously, we have demonstrated that the activation of the GPR40/free fatty acid receptor 1 (GPR40/FFAR1) signaling may play an important role in the regulation of the descending pain control system. Here, we examined the involvement of hypothalamic GPR40/FFAR1 signaling in the development of chronic pain. We used GPR40/FFAR1 knock out (GPR40KO) mice or wild type (WT) mice. A plantar incision was performed in mice. The complete Freund’s adjuvant (CFA) was intraplantary injected in mice. Mechanical allodynia and thermal hyperalgesia were evaluated using von Frey filaments and plantar test, respectively. The repeated administration of GW1100, a GPR40/FFAR1 antagonist, CFA or incision-induced mechanical allodynia compared to vehicle treated mice. The repeated GW1100 treated mice significantly increased phosphorylated ERK (p-ERK) in the spinal cord after low threshold touch stimulation. The level of the hypothalamic docosahexaenoic acid (DHA), a GPR40/FFAR1 agonist, significantly increased at 2 days after surgery compared to sham group. Furthermore, GPR40KO mice were exacerbated incision-induced mechanical allodynia, but not thermal hyperalgesia compared to WT mice. Our findings suggest that the dysfunction of this signaling pathway may be associated with the development of chronic pain.Previously, we have demonstrated that the activation of the GPR40/free fatty acid receptor 1 (GPR40/FFAR1) signaling may play an important role in the regulation of the descending pain control system. Here, we examined the involvement of hypothalamic GPR40/FFAR1 signaling in the development of chronic pain. We used GPR40/FFAR1 knock out (GPR40KO) mice or wild type (WT) mice. A plantar incision was performed in mice. The complete Freund’s adjuvant (CFA) was intraplantary injected in mice. Mechanical allodynia and thermal hyperalgesia were evaluated using von Frey filaments and plantar test, respectively. The repeated administration of GW1100, a GPR40/FFAR1 antagonist, CFA or incision-induced mechanical allodynia compared to vehicle treated mice. The repeated GW1100 treated mice significantly increased phosphorylated ERK (p-ERK) in the spinal cord after low threshold touch stimulation. The level of the hypothalamic docosahexaenoic acid (DHA), a GPR40/FFAR1 agonist, significantly increased at 2 days after surgery compared to sham group. Furthermore, GPR40KO mice were exacerbated incision-induced mechanical allodynia, but not thermal hyperalgesia compared to WT mice. Our findings suggest that the dysfunction of this signaling pathway may be associated with the development of chronic pain. PT641 Genome-wide association study identifies candidate loci associated with postoperative fentanyl requirements after laparoscopic-assisted colectomy Daisuke Nishizawa1, Kojiro Amano1, Jun Ariyama3, Junko Hasegawa1, Masakazu Hayashida2, Kazutaka Ikeda1, Horikazu Imanishi3, Toshimasa Ishii3, Kazushi Itoh3, Shinya Kasai1, Akira Kitamura3, Tsutomu Mieda3, Hideyuki Nakagawa3, Jo Tashiro3, Kazuhisa Terao3, Miki Tsujita3, Shigeki Yamaguchi3, Hiroaki Yoshikawa3 1Tokyo Metropolitan Institute of Medical Science, Japan, 2Juntendo University, Japan, 3Saitama Medical University International Medical