Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Dental Research Institute and Department of Neurobiology & Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Neuropharmacology. 2018 Jun;135:572-580. doi: 10.1016/j.neuropharm.2018.04.009. Epub 2018 Apr 7.
Unlike in the central nervous system (CNS), in the adult peripheral nervous system (PNS), activation of GABA receptors (GABAR) is excitatory because of the relatively high concentration of intracellular chloride in these neurons. Indeed, exogenous GABA and muscimol, a GABAR agonist, exacerbate acute inflammatory hypersensitivity in rodents. However, it remains unclear whether peripheral GABAR and the endogenous GABA play an important role in persistent inflammatory hypersensitivity. In this study, we thus investigated how peripheral GABAR affects pain hypersensitivity by using the complete Freund's adjuvant (CFA)-induced persistent inflammatory pain mouse model. We found that intraplantar (i.pl.) administration of GABAR antagonists, picrotoxin, and 1(S),9(R)-(-)-bicuculline methiodide significantly inhibited both spontaneous nociceptive (paw licking and flinching) behavior and mechanical hypersensitivity in CFA-injected mice at day 3 (D3), but not in naïve mice. Interestingly, CFA-induced mechanical hypersensitivity was significantly reversed by anti-GABA antibody (anti-GABA, i.pl.). In addition, RT-qPCR revealed that glutamate decarboxylase Gad1 (GAD 67) and Gad2 (GAD 65) mRNA expression was also upregulated in the ipsilateral hind paw of CFA-injected mice at D3. Finally, 5α-pregnan-3α-ol-20-one (3α,5α-THP), a selective positive allosteric modulator of GABAR, produced mechanical hypersensitivity in naïve mice in a dose-dependent manner. Taken together, our results indicate that peripheral GABAR and endogenous GABA, possibly produced by the inflamed tissue, potentiate CFA-induced persistent inflammatory hypersensitivity, suggesting that they can be used as a therapeutic target for alleviating inflammatory pain.
与中枢神经系统（CNS）不同，在成年周围神经系统（PNS）中，由于这些神经元细胞内氯离子浓度相对较高，GABA 受体（GABAR）的激活是兴奋性的。事实上，外源性 GABA 和 GABAR 激动剂 muscimol 会加剧啮齿动物的急性炎症性过敏。然而，外周 GABAR 和内源性 GABA 是否在持续性炎症性过敏中发挥重要作用仍不清楚。在这项研究中，我们使用完全弗氏佐剂（CFA）诱导的持续性炎症性疼痛小鼠模型，研究了外周 GABAR 如何影响疼痛过敏。我们发现，GABAR 拮抗剂 picrotoxin 和 1(S),9(R)-(-)-bicuculline methiodide 皮内给药可显著抑制 CFA 注射后第 3 天（D3）的自发性疼痛（舔足和退缩）行为和机械性超敏反应，但对未处理的小鼠没有作用。有趣的是，抗 GABA 抗体（anti-GABA，皮内注射）显著逆转了 CFA 诱导的机械性超敏反应。此外，RT-qPCR 显示，谷氨酸脱羧酶 Gad1（GAD 67）和 Gad2（GAD 65）mRNA 表达在 CFA 注射后第 3 天也在上肢后足上调。最后，5α-孕烷-3α-醇-20-酮（3α,5α-THP），GABAR 的选择性正变构调节剂，以剂量依赖性方式在未处理的小鼠中产生机械性超敏反应。总之，我们的结果表明，外周 GABAR 和内源性 GABA（可能由炎症组织产生）增强了 CFA 诱导的持续性炎症性过敏，这表明它们可作为缓解炎症性疼痛的治疗靶点。
