Bagdas Deniz, Wilkerson Jenny L, Kulkarni Abhijit, Toma Wisam, AlSharari Shakir, Gul Zulfiye, Lichtman Aron H, Papke Roger L, Thakur Ganesh A, Damaj M Imad
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey.
Br J Pharmacol. 2016 Aug;173(16):2506-20. doi: 10.1111/bph.13528. Epub 2016 Jul 18.
Orthosteric agonists and positive allosteric modulators (PAMs) of the α7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function.
Initial studies examined the α7 ago-PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model.
Complementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through α7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test.
Collectively, these results provide the first proof of principle that α7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain.
α7烟碱型乙酰胆碱受体（nAChR）的正构激动剂和正变构调节剂（PAMs）是调节疼痛的新型治疗方法。此外，具有变构激动剂和PAMs双重功能的化合物，即前体PAMs，可进一步调节受体功能。
初步研究在福尔马林、完全弗氏佐剂（CFA）、脂多糖炎症性疼痛模型、慢性压迫性损伤神经性疼痛模型以及甩尾和热板急性热痛觉测定中检测了α7前体PAM GAT107。其他研究在CFA模型中检测了GAT107的作用位点以及脊髓背角中的免疫组化标志物。
互补的药理学和遗传学方法证实，GAT107的剂量依赖性抗伤害感受作用是通过α7 nAChR介导的。然而，GAT107在甩尾和热板试验中无活性。此外，GAT107可阻断由醋酸注射引起的条件性位置厌恶。此外，鞘内注射而非足底注射GAT107可逆转CFA模型中的伤害感受，提示其作用部位在脊髓。免疫组化评估显示，CFA处理的小鼠脊髓中星形胶质细胞特异性胶质纤维酸性蛋白和磷酸化p38MAPK的表达增加，而鞘内注射GAT107可使其减弱。重要的是，GAT107不会引起运动障碍，并且在福尔马林试验的两个阶段亚慢性给药后仍能产生抗伤害感受作用。
总体而言，这些结果首次证明了α7前体PAMs是治疗炎症性和神经性疼痛的有效药理学策略。
