title: Antinociception of spirocyclopiperazinium salt compound LXM-10-M targeting α7 nicotinic receptor and M4 muscarinic receptor and inhibiting CaMKIIα/CREB/CGRP signaling pathway in mice.
abstract: The present study was designed to investigate the antinociception of spirocyclopiperazinium salt compound LXM-10-M (2,4-dimethyl-9-β-m-hydroxyphenylethyl-3-oxo-6, 9-diazaspiro [5.5] undecane chloride) in thermal and chemical pain models, and further to explore the molecular target and potential signal pathway. We assessed the antinociception of LXM-10-M in hot-plate test, formalin test and acetic acid writhing test in mice. The possible changes of calcium/calmodulin-dependent protein kinase IIα (CaMKIIα)/cAMP response element-binding protein (CREB)/calcitonin gene related peptide (CGRP) signaling pathway were detected by Western Blot in mice. Administration of LXM-10-M produced significant antinociception in hot-plate test, formalin test and acetic acid writhing test in mice, with no obvious toxicity. The antinociceptive effects were blocked by pretreatment with methyllycaconitine citrate (MLA, α7 nicotinic receptor antagonist) or tropicamide (TRO, M4 muscarinic receptor antagonist). Western blot analysis showed that the upregulations of p-CaMKIIα, p-CREB and CGRP in the spinal cord were reduced by LXM-10-M in chemical pain model in mice, and the effects were blocked by MLA or TRO pretreatment. This is the first paper to report that LXM-10-M exerted significant antinociception, which may be attributed to the activation of α7 nicotinic receptor and M4 muscarinic receptor and thereby triggering the inhibition of CaMKIIα/CREB/CGRP signaling pathway in mice.
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wan
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Medical and Healthy Analysis Center, Peking University, Beijing, China.
authors.forename: YiMin
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: RunTao
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China. Electronic address: yejia@bjmu.edu.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Ye
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D012492:Salts / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C547090:2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro(5.5)undecane chloride; D000700:Analgesics; D017362:Cyclic AMP Response Element-Binding Protein; D010879:Piperazines; D043588:Receptor, Muscarinic M4; D012492:Salts; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015740:Calcitonin Gene-Related Peptide
keywords: Acetic acid (PubChem CID:176); Antinociception; Aspirin (PubChem CID: 2244); CaMKIIα/CREB/CGRP signaling pathway; Formalin (PubChem CID: 712); M4 muscarinic receptor; Methoctramine (PubChem CID: 107759); Methyllycaconitine (PubChem CID: 494471); Morphine (PubChem CID: 5288826); Spirocyclopiperazinium salt compound LXM-10-M; Tropicamide (PubChem CID: 5593); α7 nicotinic receptor