Protective effects of atorvastatin against morphine-induced tolerance and dependence in mice

Background: In this study, we evaluated the effects of atorvastatin, a lipid-lowering medication on morphine-induced tolerance and dependence in mice. Methods: Tolerance was induced by subcutaneous administration of morphine (20 mg/kg) to animals, twice a day for 9 days. Atorvastatin was given at the doses of 5, 10 and 20 mg/kg, 30 min before each morphine administration, once daily for 9 days. Hot plate test was employed to assess antinociceptive effect of morphine on days 1, 3, 5, 7 and 9. Dependence was evaluated by naloxone-precipitated withdrawal syndrome. We attempted to verify withdrawal regulation of induced nitric oxide synthase (iNOS), astroglia marker, glial fibrillary acidic protein (GFAP), ionized calcium-binding protein (lbal), a microglia activation marker, a pro-inflammatory mediator, tumor necrosis alpha (TNF-alpha) and immune receptor, toll like receptor 4 (TLR-4) genes by real-time polymerase chain reaction (RT-PCR). Lipid peroxidation was estimated by assessing malondialdehyde (MDA) content in the spinal cord of animals. Results: Tolerance to antinociceptive effects of morphine was observed on days 7 and 9. Decrease in morphine-induced antinociception was reversed by concomitant intraperitoneal administration of atorvastatin (10 and 20 mg/kg). Atorvastatin (10 and 20 mg/kg) mitigated naloxone-induced withdrawal parameters. Brain expression levels of TNF-a, GFAP, Iba1 and iNOS increased in morphine withdrawn animals which were attenuated by nine days treatment with atorvastatin. Increased MDA was also normalized in withdrawn animals received atorvastatin. Conclusion: Atorvastatin exhibits meaningful protective effects against both tolerance to antinociceptive effects of morphine and withdrawal-induced behavioral profile. Neuroprotective effects of atorvastatin is further supported via inhibition of glia activity and antioxidant effects. (C) 2017 Elsevier B.V. All rights reserved.