title: The Induction of Heme Oxygenase 1 Decreases Painful Diabetic Neuropathy and Enhances the Antinociceptive Effects of Morphine in Diabetic Mice.
abstract: Painful diabetic neuropathy is a common complication of diabetes mellitus which is poorly controlled by conventional analgesics. This study investigates if treatment with an heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the allodynia and hyperalgesia induced by diabetes and enhanced the antinociceptive effects of morphine. In a diabetic mice model induced by the injection of streptozotocin (STZ), we evaluated the antiallodynic and antihyperalgesic effects produced by the intraperitoneal administration of 5 and 10 mg/kg of CoPP at several days after its administration. The antinociceptive actions produced by the systemic administration of morphine alone or combined with CoPP were also evaluated. In addition, the effects of CoPP treatment on the expression of HO-1, the microglial activation marker (CD11b/c), the inducible nitric oxide synthase (NOS2) and μ-opioid receptors (MOR), were also assessed. Our results showed that the administration of 10 mg/kg of CoPP during 5 consecutive days completely blocked the mechanical and thermal hypersensitivity induced by diabetes. These effects are accompanied by the increased spinal cord, dorsal root ganglia and sciatic nerve protein levels of HO-1. In addition, the STZ-induced activation of microglia and overexpression of NOS2 in the spinal cord were inhibited by CoPP treatment. Furthermore, the antinociceptive effects of morphine were enhanced by CoPP treatment and reversed by the administration of an HO-1 inhibitor, tin protoporphyrin IX (SnPP). The spinal cord expression of MOR was also increased by CoPP treatment in diabetic mice. In conclusion, our data provide the first evidence that the induction of HO-1 attenuated STZ-induced painful diabetic neuropathy and enhanced the antinociceptive effects of morphine via inhibition of microglia activation and NOS2 overexpression as well as by increasing the spinal cord levels of MOR. This study proposes the administration of CoPP alone or combined with morphine as an interesting therapeutic approach for the treatment of painful diabetic neuropathy.
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Castany
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Carcolé
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Leánez
authors.affiliation: Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau & Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Pol
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology
chemical_list: D000700:Analgesics; D039481:CD11b Antigen; D039521:CD11c Antigen; D008665:Metalloporphyrins; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D009020:Morphine; C032628:tin protoporphyrin IX; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1