Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40.
Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40.
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DOI：
10.1186/s12990-015-0003-8
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发表时间：
2015-02-12
期刊：
影响因子：
3.3
通讯作者：
Miyata A
中科院分区：
文献类型：
--
作者：
Karki P;Kurihara T;Nakamachi T;Watanabe J;Asada T;Oyoshi T;Shioda S;Yoshimura M;Arita K;Miyata A
G蛋白偶联受体40（GPR 40）被认为是中长链游离脂肪酸的跨膜受体，并在游离脂肪酸介导的葡萄糖刺激的胰腺胰岛素分泌增强中发挥作用。然而，GPR 40在神经系统包括躯体感觉疼痛信号传导中的功能作用尚未得到充分研究。鞘内注射GPR 40激动剂（MEDICA 16或GW 9508）剂量依赖性地减少CFA和SNL模型中的同侧机械性异常性疼痛和角叉菜胶模型中的热痛觉过敏。这些抗异常性疼痛和抗痛觉过敏的作用几乎完全逆转的GPR 40拮抗剂，GW 1100。免疫组化分析显示GPR 40在脊髓背角和背根神经节神经元中表达，免疫印迹分析显示角叉菜胶或CFA炎症或脊髓神经损伤导致GPR 40在这些区域的表达增加。来自脊髓切片的膜片钳记录显示，MEDICA 16或GW 9508的浴应用显著降低了三种疼痛模型的胶状质神经元中的自发兴奋性突触后电流的频率。我们的研究结果表明，GPR 40信号通路在炎症或神经损伤后的脊髓伤害性感受过程中起着重要的抑制作用，GPR 40激动剂可能作为一类新的镇痛药用于治疗炎症和神经病理性疼痛。本文的在线版本（doi：10.1186/s12990-015-0003-8）包含补充材料，可供授权用户使用。
The G-protein-coupled receptor 40 (GPR40) is suggested to function as a transmembrane receptor for medium- to long-chain free fatty acids and is implicated to play a role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion from pancreas. However, the functional role of GPR40 in nervous system including somatosensory pain signaling has not been fully examined yet. Intrathecal injection of GPR40 agonist (MEDICA16 or GW9508) dose-dependently reduced ipsilateral mechanical allodynia in CFA and SNL models and thermal hyperalgesia in carrageenan model. These anti-allodynic and anti-hyperalgesic effects were almost completely reversed by a GPR40 antagonist, GW1100. Immunohistochemical analysis revealed that GPR40 is expressed in spinal dorsal horn and dorsal root ganglion neurons, and immunoblot analysis showed that carrageenan or CFA inflammation or spinal nerve injury resulted in increased expression of GPR40 in these areas. Patch-clamp recordings from spinal cord slices exhibited that bath-application of either MEDICA16 or GW9508 significantly decreased the frequency of spontaneous excitatory postsynaptic currents in the substantia gelatinosa neurons of the three pain models. Our results indicate that GPR40 signaling pathway plays an important suppressive role in spinal nociceptive processing after inflammation or nerve injury, and that GPR40 agonists might serve as a new class of analgesics for treating inflammatory and neuropathic pain. The online version of this article (doi:10.1186/s12990-015-0003-8) contains supplementary material, which is available to authorized users.
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影响因子：
9.3
作者：
Dubový P;Brázda V;Klusáková I;Hradilová-Svíženská I
通讯作者：
Hradilová-Svíženská I
影响因子：
5.3
作者：
Myers, RR;Heckman, HM;Rodriguez, M
通讯作者：
Rodriguez, M
影响因子：
2.5
作者：
Ma, C;Shu, YS;LaMotte, RH
通讯作者：
LaMotte, RH
影响因子：
4.8
作者：
Feng, DD;Luo, ZQ;Chen, C
通讯作者：
Chen, C
影响因子：
7.4
作者：
KAYSER, V;GUILBAUD, G
通讯作者：
GUILBAUD, G