title: Treatment with a carbon monoxide-releasing molecule inhibits chronic inflammatory pain in mice: nitric oxide contribution.
abstract: BACKGROUND
  Carbon monoxide synthetized by inducible heme oxygenase (HO-1) exerts potent anti-inflammatory and antinociceptive effects during acute and neuropathic pain, but its role in the modulation of chronic inflammatory pain and the possible involvement of nitric oxide in this action remain unknown.
  
  
  OBJECTIVE
  The antiallodynic and antihyperalgesic effects of a carbon monoxide releasing molecule, tricarbonyldichlororuthenium(II) dimer (CORM-2), daily administered from days 4 to 14 after complete Freund's adjuvant (CFA) injection in wild-type (WT), neuronal (NOS1-KO), and inducible (NOS2-KO) nitric oxide synthases knockout mice, were evaluated using von Frey filaments and plantar tests. Effects of CORM-2 treatment on the expression of HO-1, NOS1, and NOS2 at 14 days after inflammation induction were assessed by Western blot.
  
  
  RESULTS
  Main inflammatory pain symptoms induced by CFA in WT, NOS1-KO, and NOS2-KO mice were significantly reduced in a time-dependent manner by CORM-2 treatment. In all genotypes, inflammation increased the dorsal root ganglia and paw expression of HO-1, but CORM-2 treatment only over-expressed this enzyme in the paw of all genotypes. The increased NOS1 expression induced by inflammation in WT mice was abolished by CORM-2 treatment, while there was no effect of the inflammation in neither CORM-2 treatment in the expression of NOS2 in WT and NOS1-KO mice.
  
  
  CONCLUSIONS
  CORM-2 treatment inhibits inflammatory pain through enhancing HO-1 paw expression in all genotypes and reducing NOS1 over-expression in WT mice. An interaction between HO-1/carbon monoxide and NOS1/nitric oxide systems was also demonstrated. CORM-2 treatment may represent a new approach for management chronic inflammatory pain.
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau & Institut de Neurociències, Facultat de Medicina. Edifici M2-115, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Negrete
authors.forename: Arnau
authors.initials: A
authors.lastname: Hervera
authors.forename: Sergi
authors.initials: S
authors.lastname: Leánez
authors.forename: Olga
authors.initials: O
authors.lastname: Pol
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D059350:Chronic Pain / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D005620:Freund's Adjuvant / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D007249:Inflammation / Q000150:complications; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D008565:Membrane Proteins; D009942:Organometallic Compounds; C447082:tricarbonyldichlororuthenium (II) dimer; D009569:Nitric Oxide; D002248:Carbon Monoxide; D005620:Freund's Adjuvant; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse