Armbruster Anja, Neumann Elena, Kötter Valentin, Hermanns Henning, Werdehausen Robert, Eulenburg Volker
Institute of Biochemistry, Emil-Fischer-Center, University of Erlangen-Nuremberg, Erlangen, Germany.
Department of Anesthesiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Front Mol Neurosci. 2018 Jan 10;10:438. doi: 10.3389/fnmol.2017.00438. eCollection 2017.
Chronic pain conditions are difficult to treat and the therapeutic outcome is frequently unsatisfactory. Changes in excitation/inhibition balance within the dorsal horn contribute to the establishment and persistence of chronic pain. Thus, facilitation of inhibitory neurotransmission is a promising approach to treat chronic pain pharmacologically. Glycine transporter 1 (GlyT1) plays an important role in regulating extracellular glycine concentrations. Aim of the present study therefore was to investigate whether the specific GlyT1 inhibitor bitopertin (RG1678; RO4917838) might constitute a novel treatment for chronic pain by facilitating glycinergic inhibition. Mechanical allodynia and thermal hyperalgesia were induced by chronic constriction injury of the sciatic nerve or carrageenan injections into the plantar surface of the hind paw in rodents. The effect of acute and long-term bitopertin application on the reaction threshold to mechanical and thermal stimuli was determined. General activity was determined in open field experiments. The glycine concentration in cerebrospinal fluid and blood was measured by HPLC. Systemic application of bitopertin in chronic pain conditions lead to a significant increase of the reaction thresholds to mechanical and thermal stimuli in a time and dose-dependent manner. Long-term application of bitopertin effectuated stable beneficial effects over 4 weeks. Bitopertin did not alter reaction thresholds to stimuli in control animals and had no effect on general locomotor activity and anxiety but lead to an increased glycine concentration in cerebrospinal fluid. These findings suggest that inhibition of the GlyT1 by bitopertin represents a promising new approach for the treatment of chronic pain.
慢性疼痛病症难以治疗，治疗效果常常不尽人意。背角内兴奋/抑制平衡的改变促成了慢性疼痛的形成和持续。因此，促进抑制性神经传递是一种有望通过药理学方法治疗慢性疼痛的途径。甘氨酸转运体1（GlyT1）在调节细胞外甘氨酸浓度方面发挥着重要作用。因此，本研究的目的是探究特异性GlyT1抑制剂比妥普汀（RG1678；RO4917838）是否可能通过促进甘氨酸能抑制作用而成为一种治疗慢性疼痛的新方法。通过坐骨神经慢性缩窄损伤或向啮齿动物后爪足底注射角叉菜胶来诱导机械性异常性疼痛和热痛觉过敏。测定急性和长期应用比妥普汀对机械和热刺激反应阈值的影响。在旷场实验中测定一般活动情况。通过高效液相色谱法测量脑脊液和血液中的甘氨酸浓度。在慢性疼痛病症中全身应用比妥普汀会导致对机械和热刺激的反应阈值以时间和剂量依赖性方式显著升高。长期应用比妥普汀在4周内产生了稳定的有益效果。比妥普汀不会改变对照动物对刺激的反应阈值，对一般运动活动和焦虑也没有影响，但会导致脑脊液中甘氨酸浓度升高。这些发现表明，比妥普汀抑制GlyT1代表了一种治疗慢性疼痛的有前景的新方法。
