title: Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice.
abstract: The development of morphine-induced antinociceptive tolerance limits its therapeutic efficacy in pain management. Atorvastatin, or competitive inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, is mainstay agent in hypercholesterolemia treatment. Beyond the cholesterol-lowering activity, exploration of neuroprotective properties of this statin indicates its potential benefit in central nervous disorders. The aim of the present study was to assess the effects of atorvastatin in development and expression of morphine-induced analgesic tolerance in male mice and probable involvement of nitric oxide. Chronic and acute treatment with atorvastatin 10 and 20mg/kg, respectively, could alleviate morphine tolerance in development and expression phases. Chronic co-administration of nitric oxide synthase (NOS) inhibitors including L-NAME (non selective NOS inhibitor; 2mg/kg), aminoguanidine (selective inducible NOS inhibitor; 50mg/kg) and 7-NI (selective neuronal NOS inhibitor; 15mg/kg) with atorvastatin blocked the protective effect of atorvastatin in tolerance reversal. Moreover, reversing the atorvastatin effect was also observed in acute simultaneous treatment of L-NAME (5mg/kg) and aminoguanidine (100mg/kg) with atorvastatin. Co-treatment of guanylyl cyclase inhibitor, ODQ (chronic dose: 10mg/kg and acute dose: 20mg/kg) was associated with prevention of atorvastatin anti-tolerance properties. Our results revealed that the atorvastatin modulating role in morphine antinociceptive tolerance is mediated at least in part via nitric oxide in animal pain models of hot plate and tail flick.
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Physiology and Pharmacology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Electronic address: mhasanipoor@gmail.com.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Hassanipour
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of pharmacology, School of medicine, Kashan University of Medical Sciences, Kashan, Iran. Electronic address: aminikhoyi@gmail.com.
authors.forename: Hossein
authors.initials: H
authors.lastname: Amini-Khoei
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Electronic address: hshafaroodi@gmail.com.
authors.forename: Hamed
authors.initials: H
authors.lastname: Shafaroodi
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: armin_shirzadian@yahoo.com.
authors.forename: Armin
authors.initials: A
authors.lastname: Shirzadian
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: nastaran.rahimee@gmail.com.
authors.forename: Nastaran
authors.initials: N
authors.lastname: Rahimi
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: muhammad_ik12@yahoo.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran-Khan
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Electronic address: rezayat1387@gmail.com.
authors.forename: Seyed-Mahdi
authors.initials: SM
authors.lastname: Rezayat
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: Dehpour@sina.tums.ac.ir.
authors.forename: Ahmadreza
authors.initials: A
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D000069059:Atorvastatin / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D009569:Nitric Oxide / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009294:Narcotics; D009569:Nitric Oxide; D009020:Morphine; D001120:Arginine; D000069059:Atorvastatin; D019331:NG-Nitroarginine Methyl Ester
keywords: Antinociception; Atorvastatin; Mice; Morphine; Nitric oxide; Tolerance