title: Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice.
abstract: BACKGROUND
  Carbon monoxide (CO) synthesized by heme oxygenase 1 (HO-1) exerts antinociceptive effects during inflammation but its role during neuropathic pain remains unknown. Our objective is to investigate the exact contribution of CO derived from HO-1 in the modulation of neuropathic pain and the mechanisms implicated.
  
  
  RESULTS
  We evaluated the antiallodynic and antihyperalgesic effects of CO following sciatic nerve injury in wild type (WT) or inducible nitric oxide synthase knockout (NOS2-KO) mice using two carbon monoxide-releasing molecules (CORM-2 and CORM-3) and an HO-1 inducer (cobalt protoporphyrin IX, CoPP) daily administered from days 10 to 20 after injury. The effects of CORM-2 and CoPP on the expression of HO-1, heme oxygenase 2 (HO-2), neuronal nitric oxide synthase (NOS1) and NOS2 as well as a microglial marker (CD11b/c) were also assessed at day 20 after surgery in WT and NOS2-KO mice. In WT mice, the main neuropathic pain symptoms induced by nerve injury were significantly reduced in a time-dependent manner by treatment with CO-RMs or CoPP. Both CORM-2 and CoPP treatments increased HO-1 expression in WT mice, but only CoPP stimulated HO-1 in NOS2-KO animals. The increased expression of HO-2 induced by nerve injury in WT, but not in NOS2-KO mice, remains unaltered by CORM-2 or CoPP treatments. In contrast, the over-expression of CD11b/c, NOS1 and NOS2 induced by nerve injury in WT, but not in NOS2-KO mice, were significantly decreased by both CORM-2 and CoPP treatments. These data indicate that CO alleviates neuropathic pain through the reduction of spinal microglial activation and NOS1/NOS2 over-expression.
  
  
  CONCLUSIONS
  This study reports that an interaction between the CO and nitric oxide (NO) systems is taking place following sciatic nerve injury and reveals that increasing the exogenous (CO-RMs) or endogenous (CoPP) production of CO may represent a novel strategy for the treatment of neuropathic pain.
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Hervera
authors.forename: Sergi
authors.initials: S
authors.lastname: Leánez
authors.forename: Roger
authors.initials: R
authors.lastname: Negrete
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Olga
authors.initials: O
authors.lastname: Pol
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055786:Gene Knockout Techniques; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D012584:Sciatic Nerve / Q000293:injuries; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen; D009942:Organometallic Compounds; D011719:Pyrazines; D011758:Pyrroles; C484301:cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine; C476530:tricarbonylchloro(glycinato)ruthenium(II); C447082:tricarbonyldichlororuthenium (II) dimer; D009569:Nitric Oxide; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1