Department of General and Thoracic Surgery, Laboratory of Experimental Surgery, Justus-Liebig-University, German Center for Lung Research [DZL], Cardio-Pulmonary Institute [CPI], Giessen, Germany.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, USA.
Neuropharmacology. 2023 Dec 1;240:109717. doi: 10.1016/j.neuropharm.2023.109717. Epub 2023 Sep 25.
Pain due to inflammation can be reduced by targeting the noncanonical nicotinic receptors (NCNR) in cells of the immune system that regulate the synthesis and release of pro- and anti-inflammatory cytokines. Although NCNR do not generate ion channel currents, the pharmacology of ion-channel forms of the receptors can predict drugs which may be effective regulators of the cholinergic anti-inflammatory system (CAS). Agonists of α7 type receptors have been definitively associated with CAS. Receptors containing α9 and α10 subunits have also been implicated. We have recently characterized two small molecules, pCN-diEPP and mCN-diEPP, as selective α9α10 agonists and antagonists, respectively. We used these drugs, along with nicotine, an α7 agonist and α9α10 antagonist, to probe the mixed populations of receptors that are formed when α7, α9, and α10 are all expressed together in Xenopus oocytes. We also evaluated the effects of the CN-diEPP compounds on regulating the ATP-induced release of interleukin-1β from monocytic THP-1 cells, which express NCNR. The compounds successfully identified separate populations of receptors when all three subunits were co-expressed, including a potential population of homomeric α10 receptors. The α9α10 agonist pCN-diEPP was the more effective regulator of interleukin-1β release in THP-1 cells. pCN-diEPP was also fully effective in a mouse model of inflammatory pain, while mCN-diEPP had only partial effects, requiring a higher dosage. The analgetic effects of pCN-diEPP and mCN-diEPP were retained in α7 knockout mice. Taken together, our results suggest that drugs that selectively activate α9α10 receptors may useful to reduce inflammatory pain through the CAS.
炎症引起的疼痛可以通过靶向调节免疫细胞中前炎和抗炎细胞因子合成和释放的非经典烟碱型受体（NCNR）来减轻。尽管 NCNR 不会产生离子通道电流，但受体的离子通道形式的药理学可以预测可能是胆碱能抗炎系统（CAS）有效调节剂的药物。α7 型受体的激动剂已被明确与 CAS 相关。含有α9 和α10 亚基的受体也有牵连。我们最近将两种小分子，pCN-diEPP 和 mCN-diEPP，分别表征为选择性α9α10 激动剂和拮抗剂。我们使用这些药物以及烟碱（α7 激动剂和α9α10 拮抗剂）来探测当α7、α9 和α10 一起在非洲爪蟾卵母细胞中表达时形成的混合受体群体。我们还评估了 CN-diEPP 化合物对调节表达 NCNR 的单核细胞 THP-1 细胞中 ATP 诱导的白细胞介素-1β释放的影响。当所有三个亚基共同表达时，这些化合物成功地鉴定了不同的受体群体，包括潜在的同源性α10 受体群体。α9α10 激动剂 pCN-diEPP 是调节 THP-1 细胞中白细胞介素-1β释放的更有效调节剂。pCN-diEPP 在炎性疼痛的小鼠模型中也完全有效，而 mCN-diEPP 仅具有部分作用，需要更高的剂量。pCN-diEPP 和 mCN-diEPP 的镇痛作用在α7 敲除小鼠中得以保留。总之，我们的结果表明，选择性激活α9α10 受体的药物可能通过 CAS 有助于减轻炎症性疼痛。
