title: Spinal NADPH oxidase is a source of superoxide in the development of morphine-induced hyperalgesia and antinociceptive tolerance.
abstract: The role of superoxide and its active byproduct peroxynitrite as mediators of nociceptive signaling is emerging. We have recently reported that nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) provides a critical source of these reactive oxygen and nitrogen species during central sensitization associated with the development of morphine-induced hyperalgesia and antinociceptive tolerance. In this study, we demonstrate that activation of spinal NADPH oxidase is another critical source for superoxide generation. Indeed, the development of morphine-induced hyperalgesia and antinociceptive tolerance was associated with increased activation of NADPH oxidase and superoxide release. Co-administration of morphine with systemic delivery of two structurally unrelated NADPH oxidase inhibitors namely apocynin or diphenyleneiodonium (DPI), blocked NADPH oxidase activation and the development of hyperalgesia and antinociceptive tolerance at doses devoid of behavioral side effects. These results suggest that activation of spinal NADPH oxidase contributes to the development of morphine-induced hyperalgesia and antinociceptive tolerance. The role of spinal NADPH oxidase was confirmed by showing that intrathecal delivery of apocynin blocked these events. Our results are the first to implicate the contribution of NADPH oxidase as an enzymatic source of superoxide and thus peroxynitrite in the development of central sensitization associated with morphine-induced hyperalgesia and antinociceptive tolerance. These results continue to support the critical role of these reactive oxygen and nitrogen species in pain while advancing our knowledge of their biomolecular sources.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Doyle
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004361:Drug Tolerance / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009020:Morphine / Q000378:metabolism / Q000633:toxicity*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013481:Superoxides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D013481:Superoxides; D009020:Morphine; D019255:NADPH Oxidases