title: Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice.
abstract: OBJECTIVE
  The parasympathetic nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of cytokines, including tumor necrosis factor alpha (TNFalpha), by activated macrophages. The vagus nerve may exert antiinflammatory actions via a specific effect of its principal neurotransmitter, acetylcholine, on the alpha7 subunit of nicotinic acetylcholine receptors (alpha7nAChR) on macrophages. The present study was undertaken to obtain insight into the role of the cholinergic antiinflammatory pathway in arthritis.
  
  
  METHODS
  To inhibit the cholinergic antiinflammatory pathway, mice were subjected to unilateral cervical vagotomy or sham surgery, after which arthritis was induced with type II collagen. In a separate study, nicotine was added to the drinking water of mice with collagen-induced arthritis (CIA). In addition, we investigated the effects of intraperitoneally (IP)-injected nicotine and the specific alpha7nAChR agonist AR-R17779.
  
  
  RESULTS
  Clinical arthritis was exacerbated by vagotomy and ameliorated by oral nicotine administration. Moreover, oral nicotine inhibited bone degradation and reduced TNFalpha expression in synovial tissue. Both IP-injected nicotine and AR-R17779 ameliorated clinical arthritis and reduced synovial inflammation. This was accompanied by a reduction of TNFalpha levels in both plasma and synovial tissue. The effect of AR-R17779 was more potent compared with that of nicotine and was associated with delayed onset of the disease as well as with protection against joint destruction.
  
  
  CONCLUSIONS
  These data provide the first evidence of a role of the cholinergic antiinflammatory pathway in the murine CIA model of rheumatoid arthritis.
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marjolein A
authors.initials: MA
authors.lastname: van Maanen
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lebre
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: LaRosa
authors.forename: Daniel
authors.initials: D
authors.lastname: Elbaum
authors.forename: Margriet J
authors.initials: MJ
authors.lastname: Vervoordeldonk
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002356:Cartilage / Q000473:pathology; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010275:Parasympathetic Nervous System / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism; D013585:Synovitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014630:Vagus Nerve / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C408128:AR-R 17779; D001952:Bridged-Ring Compounds; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine