title: The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain.
abstract: Both pharmacologic and genetic approaches have been used to study the involvement of the muscarinic acetylcholine system in the regulation of chronic pain. Previous studies suggest that the M2 and M4 subtypes of muscarinic acetylcholine receptors (mAChRs) are important targets for the development of chronic pain. (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] octane (PTAC) has agonist effects on muscarinic M2 and M4 receptors and antagonist effects on muscarinic M1, M3, and M5 receptors. However, its analgesic effects have been less studied.
  
  
  
  Male C57B L/6 mice were anesthetized, and left common peroneal nerve (CPN) ligation was performed to induce neuropathic pain. Before and after the application of PTAC systemically or specifically to the anterior cingulate cortex (ACC), the withdrawal thresholds to mechanical stimulation and static weight balance were measured, and the effects of PTAC on the conditioned place preference (CPP) were further evaluated. Western blotting was used to examine the expression of M1 and M2 in the striatum, ACC, and ventral tegmental area.
  
  
  
  The application of PTAC ([i.p.] intraperitoneal injection) increased the paw withdraw threshold in both the early (0.05 mg/kg, mean difference [95% confidence interval, CI]: 0.19 [0.05-0.32]; 0.10 mg/kg: mean difference [95% CI]: 0.34 [0.22-0.46]) and the late phases (0.05 mg/kg: mean difference [95% CI]: 0.45 [0.39-0.50]; 0.1 mg/kg: mean difference [95% CI]: 0.44 [0.37-0.51]) after nerve injury and rebalanced the weight distribution on the hind paws of mice (L/R ratio: before, 0.56 ± 0.03. 0.05 mg/kg, 1.00 ± 0.04, 0.10 mg/kg, 0.99 ± 0.03); however, it failed to induce place preference in the CPP (0.05 mg/kg, 2-way analysis of variance, P > .05; 0.2 mg/kg, 2-way analysis of variance, P > .05,). At the same doses, the analgesic effects at D3-5 lasted longer than the effects at D14-16. This may be due to the down-regulation of the M2 and M1 in tested brain regions.
  
  
  
  These observations suggested that PTAC has analgesic effects on the neuropathic pain induced by nerve injury.
authors.affiliation: From the *Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China; †Institute of Neuroscience and Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; ‡Department of Neurosurgery, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China; §Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China; and ‖Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Wang
authors.forename: Zhen-Xing
authors.initials: ZX
authors.lastname: Zuo
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Feng
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Xiang-Yao
authors.initials: XY
authors.lastname: Li
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011976:Receptors, Muscarinic / Q000096:biosynthesis; D013830:Thiadiazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C115974:6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo(3.2.1)octane; D000700:Analgesics; D001643:Bridged Bicyclo Compounds; D011976:Receptors, Muscarinic; D013830:Thiadiazoles