Schuelert Niklas, Just Stefan, Kuelzer Raimund, Corradini Laura, Gorham Louise C J, Doods Henri
Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
Eur J Pharmacol. 2015 Jan 5;746:274-81. doi: 10.1016/j.ejphar.2014.11.003. Epub 2014 Nov 12.
Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund׳s Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24 h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1 mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100 µM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.
生长抑素（SST）是一种肽类激素，它通过与G蛋白偶联的SST受体相互作用并抑制不同激素的释放来调节内分泌系统并影响神经传递。本研究的目的是调查选择性SSTR4激动剂J-2156的镇痛特性是否通过外周和/或脊髓受体介导。在腹腔注射J-2156后，测量其对完全弗氏佐剂（CFA）模型中机械性痛觉过敏的影响。在向Wistar大鼠爪部注射CFA或赋形剂24小时后进行电生理神经元记录。在全身或脊髓应用J-2156后，测量隐神经外周传入纤维以及脊髓广动力范围（WDR）和伤害性特异性（NS）神经元的机械敏感性。在行为学研究中，J-2156在CFA动物中剂量依赖性地减轻痛觉过敏。最小有效剂量为0.1mg/kg。J-2156显著降低外周传入纤维和脊髓神经元的机械敏感性。J-2156对NS神经元有剂量依赖性抑制作用，而在WDR神经元中，只有最高浓度100μM才有作用。在假手术对照组中，J-2156对神经元活动没有影响。我们证明，J-2156在CFA大鼠模型中剂量依赖性地降低外周和脊髓神经元兴奋性，而不影响生理性疼痛传递。鉴于抑制脊髓神经元所需的化合物浓度较高，CFA模型中观察到的行为效应不太可能是由中枢介导的。总体而言，这些数据表明J-2156的镇痛作用主要通过外周SST4受体介导。
