title: Comparison of nitric oxide synthase inhibitors, phospholipase A2 inhibitor and free radical scavengers as attenuators of opioid withdrawal syndrome.
abstract: Chronic morphine-induced withdrawal syndrome after morphine cessation remains a severe obstacle in the clinical treatment of morphine. Previous studies have shown that nitric oxide synthetase (NOS) inhibitors may have therapeutic potential in morphine withdrawal in humans. The mechanisms that underlie expression of morphine-induced withdrawal syndrome are, however, not yet fully understood. Therefore, this study was designed to determine the mechanism of the expression of morphine-induced withdrawal syndrome in mice. Morphine-dependent mice showed marked body weight loss and several withdrawal signs after naloxone challenge. Pretreatment with a NOS inhibitor, such as N-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole, but not aminoguanidine, significantly attenuated the expression of morphine-induced withdrawal syndrome. Furthermore, mepacrine (a phospholipase A2 inhibitor) significantly attenuated the morphine-induced withdrawal syndrome in a manner that was different than that with a NOS inhibitor. These results suggest that nNOS and phospholipase A2, which might increase free radicals, play an important role in the expression of morphine-induced withdrawal syndrome. On the contrary, free radical scavengers (including fullerenes, ascorbate-2-phosphate, and DL-alpha-tocopheryl phosphate) attenuated the expression of the morphine-induced withdrawal syndrome. These results indicate that free radicals play an important role in the expression of physical dependence on morphine, and fullerenes could be a potential clinical tool in the relief of morphine withdrawal syndrome.
authors.affiliation: Department of Legal Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Shinobu
authors.initials: S
authors.lastname: Ito
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsubayashi
authors.forename: Toshiko
authors.initials: T
authors.lastname: Sawaguchi
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D017665:Hydroxyl Radical; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D009270:Naloxone / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D064801:Phospholipase A2 Inhibitors; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D013481:Superoxides / Q000378:metabolism; D024502:alpha-Tocopherol / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D064801:Phospholipase A2 Inhibitors; D013481:Superoxides; C011669:ascorbate-2-phosphate; D017665:Hydroxyl Radical; D009270:Naloxone; C012552:alpha-tocopherol phosphate; D019001:Nitric Oxide Synthase; D024502:alpha-Tocopherol; D001205:Ascorbic Acid; D019331:NG-Nitroarginine Methyl Ester