title: The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice.
abstract: The activation of cannabinoid 2 receptors (CB2R) attenuates chronic pain, but the role played by carbon monoxide synthesized by the inducible heme oxygenase 1 (HO-1) on the anti-nociceptive effects produced by a selective CB2R agonist, JWH-015, during painful diabetic neuropathy remains unknown.
  
  
  
  In streptozotocin (STZ)-induced diabetic mice, the anti-allodynic and anti-hyperalgesic effects of the subcutaneous administration of JWH-015 alone or combined with the intraperitoneal administration of a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer (CORM-2)) or an HO-1 inducer compound (cobalt protoporphyrin IX (CoPP)) at 10 mg/kg were evaluated. Reversion of JWH-015 anti-nociceptive effects by the administration of an HO-1 inhibitor (tin protoporphyrin IX (SnPP)) and a CB2R antagonist (AM630) was also evaluated. Furthermore, the protein levels of HO-1, neuronal nitric oxide synthase (NOS1), and CB2R in diabetic mice treated with CORM-2 and CoPP alone or combined with JWH-015 were also assessed.
  
  
  
  The administration of JWH-015 dose dependently inhibited hypersensitivity induced by diabetes. The effects of JWH-015 were enhanced by their coadministration with CORM-2 or CoPP and reversed by SnPP or AM630. The increased protein levels of HO-1 induced by CORM-2 and CoPP treatments were further enhanced in JWH-015-treated mice. All treatments similarly enhanced the peripheral expression of CB2R and avoided the spinal cord over-expression of NOS1 induced by diabetes.
  
  
  
  The activation of HO-1 enhanced the anti-nociceptive effects of JWH-015 in diabetic mice, suggesting that coadministration of JWH-015 with CORM-2 or CoPP might be an interesting approach for the treatment of painful diabetic neuropathy in mice.
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau and Institut de Neurociències. Facultat de Medicina, Edifici M2-115, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Castany
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau and Institut de Neurociències. Facultat de Medicina, Edifici M2-115, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Carcolé
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau and Institut de Neurociències. Facultat de Medicina, Edifici M2-115, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Leánez
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau and Institut de Neurociències. Facultat de Medicina, Edifici M2-115, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. opol@santpau.es.
authors.forename: Olga
authors.initials: O
authors.lastname: Pol
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006930:Hyperalgesia / Q000188:drug therapy; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis / Q000235:genetics; D009942:Organometallic Compounds / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000096:biosynthesis* / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000700:Analgesics; D007211:Indoles; D008665:Metalloporphyrins; D009942:Organometallic Compounds; D011524:Protoporphyrins; D043885:Receptor, Cannabinoid, CB2; C447082:tricarbonyldichlororuthenium (II) dimer; C007095:cobaltiprotoporphyrin; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D051547:Heme Oxygenase-1; C094023:iodopravadoline; C402944:JHW 015
keywords: Analgesia; Cannabinoid receptors; Carbon monoxide; Diabetes; Heme oxygenases; Nitric oxide synthases; Painful diabetic neuropathy