Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea.
Department of Orofacial Pain and Oral Medicine, School of Dentistry, Yonsei University, Seoul, South Korea.
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:100-9. doi: 10.1016/j.pnpbp.2014.10.011. Epub 2014 Oct 30.
In our current study, we investigated the role of spinal glutamate recycling in the development of orofacial inflammatory pain. DL-threo-β-benzyloxyaspartate (TBOA) or methionine sulfoximine (MSO) was administered intracisternally to block spinal glutamate transporter and glutamine synthetase activity in astroglia. Intracisternal administration of high dose TBOA (10 μg) produced thermal hyperalgesia in naïve rats but significantly attenuated the thermal hyperalgesia in rats that had been pretreated with interleukin (IL)-1β or Complete Freund's Adjuvant (CFA). In contrast, intracisternal injection of MSO produced anti-hyperalgesic effects against thermal stimuli in CFA-treated rats only. To confirm the paradoxical antinociceptive effects of TBOA and MSO, we examined changes in c-Fos expression in the medullary dorsal horn produced by thermal stimulation in naïve, IL-1β-, or CFA-treated rats, after intracisternal injections of TBOA and MSO. Intracisternal administration of TBOA significantly increased c-Fos immunoreactivity in naïve rats. In contrast, intracisternal administration of TBOA significantly decreased the up-regulation of c-Fos immunoreactivity in the medullary dorsal horn of IL-1β- and CFA-treated rats. However, intracisternal injection of MSO blocked the up-regulation of c-Fos immunoreactivity in CFA-treated rats only. We also investigated the effects of botulinum toxin type A (BoNT-A) on TBOA-induced paradoxical antinociception in CFA-treated rats, as BoNT-A inhibits the release of neurotransmitters, including glutamate. BoNT-A treatment reversed behavioral responses produced by intracisternal administration of TBOA in CFA-treated rats. These results suggest that the paradoxical responses produced by blocking glutamate transporters under inflammatory pain conditions are mediated by the modulation of glutamate release from presynaptic terminals. Moreover, blockade of glutamate reuptake could represent a new therapeutic target for the treatment of chronic inflammatory pain conditions.
在我们目前的研究中，我们研究了脊髓谷氨酸再循环在口腔炎性疼痛发展中的作用。DL-threo-β-苯甲氧基天冬氨酸（TBOA）或甲硫氨酸亚砜亚胺（MSO）被鞘内给药以阻断星形胶质细胞中的脊髓谷氨酸转运体和谷氨酰胺合成酶活性。高剂量 TBOA（10 μg）鞘内给药在未处理的大鼠中产生热痛觉过敏，但显着减轻了预先用白细胞介素（IL）-1β或完全弗氏佐剂（CFA）处理的大鼠的热痛觉过敏。相比之下，MSO 的鞘内注射仅对 CFA 处理的大鼠产生抗热刺激的抗痛觉过敏作用。为了证实 TBOA 和 MSO 的矛盾镇痛作用，我们检查了鞘内注射 TBOA 和 MSO 后，热刺激引起的幼稚、IL-1β-或 CFA 处理大鼠的延髓背角中 c-Fos 表达的变化。鞘内给予 TBOA 显着增加了幼稚大鼠的 c-Fos 免疫反应性。相反，鞘内给予 TBOA 显着降低了 IL-1β-和 CFA 处理大鼠背角中 c-Fos 免疫反应性的上调。然而，仅鞘内注射 MSO 阻断了 CFA 处理大鼠的 c-Fos 免疫反应性的上调。我们还研究了肉毒杆菌毒素 A（BoNT-A）对 CFA 处理大鼠 TBOA 诱导的矛盾镇痛作用的影响，因为 BoNT-A 抑制神经递质，包括谷氨酸的释放。BoNT-A 治疗逆转了 CFA 处理大鼠鞘内给予 TBOA 引起的行为反应。这些结果表明，在炎症性疼痛条件下阻断谷氨酸转运体引起的矛盾反应是通过调节突触前末梢谷氨酸的释放来介导的。此外，阻断谷氨酸再摄取可能代表治疗慢性炎症性疼痛的新治疗靶点。
