Antinociception of the spirocyclopiperazinium salt compound LXM-15 via activating α7 nAChR and M4 mAChR and inhibiting CaMKIIa/cAMP/CREB/CGRP signalling pathway in mice

作者：Yang, Hua; Sun, Qi; Liang, Yingying; Jiang, Yimin; Li, Runtao; Ye, Jia^*

来源：Regulatory Toxicology and Pharmacology, 2018, 94: 108-114.

DOI：10.1016/j.yrtph.2018.01.012

• Spirocyclopiperazinium salt compound
• LXM-15
• Antinociception
• alpha 7 nicotinic acetylcholine receptor
• M4 muscarine acetylcholine receptor
• CaMKIIa/cAMP/CREB/CGRP signalling pathway

The aim of this study was to investigate the analgesic effect of the spirocyclopiperazinium salt compound LXM-15 by intragastric administration in thermal and chemical pain models and further to elucidate the possible molecular mechanisms. The results showed that LXM-15 exerted significant antinociception in hot-plate test, formalin test and acetic acid writhing test. Western blot analysis showed that LXM-15 significantly reduced the upregulation of phosphorylation of calcium/calmodulin -dependent protein kinase II alpha (CaMKII alpha) and cAMP response element-binding protein (CREB), and further decreased the elevation of calcitonin gene related peptide (CGRP) in the dorsal root ganglion (DRG) and spinal cord in mice. ELISA analysis showed the level of cAMP in the spinal cord was decreased by LXM-15. All effects of LXM-15 could be blocked by methyllycaconitine citrate (MLA, a selective alpha 7 nicotinic receptor antagonist) or tropicamide (TRO, a selective M4 muscarinic receptor antagonist). This study first reported that intragastric administration of LXM-15 produced significant analgesic effect, which may be related to the activation of alpha 7 nicotinic acetylcholine receptor and M4 muscarine acetylcholine receptor, and thereby inhibiting CaMKIIa/cAMP/CREB/CGRP signalling pathway.

• 出版日期2018-4
• 单位北京大学