Nasim Sadat Pajohanfar1, Ehsan Mohebbi1, Ahmad Hosseini-Bandegharaei2, Mohamadraza Amin3, Golnaz Vaseghi4, Bahareh Amin5. 1. Student Research Committee, Sabzevar University of Medical Sciences, Sabzevar, Iran. 2. Department of Environmental Health Engineering, School of Public Health, Sabzevar University of Medical Sciences, Sabzevar, Iran; Department of Engineering, Kashmar Branch, Islamic Azad University, PO Box 161, Kashmar, Iran. 3. Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands. 4. Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. 5. Cellular and Molecular Research Center, Department of Physiology and Pharmacology, Faculty of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran. Electronic address: aminb@medsab.ac.ir.
Abstract
BACKGROUND: Tolerance to analgesic effects of opioids and dependence to them are main concerns in the treatment of chronic pain conditions, limiting clinical application of these drugs. This study aimed to evaluate the effect of simvastatin on the morphine-induced tolerance and dependence in mice. MATERIAL AND METHODS: For this purpose, mice were treated with either daily morphine (20 mg/kg, s.c.) alone, or in combination with simvastatin (2.5, 5 and 10mg/kg, i.p.), for 9 continuous days. Antinociceptive effect of morphine was assessed through measuring latency time withdrawal of paw exposed to thermal stimulus, in the hot plate test. Naloxone-precipitated morphine withdrawal (5mg/kg, i.p.), was used for dependence evaluation. Changes in brain gene expression levels of induced nitric oxide synthase (iNOS), astroglia marker, glial fibrillary acidic protein (GFAP), ionized calcium-binding protein (Iba1) a microglia activation marker, a pro-inflammatory mediator and tumor necrosis alpha (TNF-α) were measured after withdrawal by real-time polymerase chain reaction (RT-PCR). RESULTS: Behavioral tests indicated that latency time increased after morphine treatment in the hot plate test. However, this effect decreased on day 7, demonstrating tolerance to antinociceptive effect of morphine. Reduced anti-nociceptive effect of morphine was returned in animals treated with simvastatin (5 and 10mg/kg) in combination with morphine. Simvastatin (5 and 10mg/kg) attenuated morphine dependence as indicated by a less severe antagonist-precipitated withdrawal syndrome. Administration of naloxone was associated with the increased expression of TNF-α, GFAP, Iba1 and iNOS in the brain samples of morphine dependent mice, while the nine days treatment with both 5 and 10mg/kg simvastatin reduced such changes. CONCLUSION: The obtained results showed that the protective effects of simvastatin against both tolerance to nociceptive effects of morphine as well as withdrawal-induced behavioral profile are meaningful. Inhibition of glia activity as well as antioxidant effects of pharmaceutical simvastatin further proves its neuroprotective property.
BACKGROUND: Tolerance to analgesic effects of opioids and dependence to them are main concerns in the treatment of chronic pain conditions, limiting clinical application of these drugs. This study aimed to evaluate the effect of simvastatin on the morphine-induced tolerance and dependence in mice. MATERIAL AND METHODS: For this purpose, mice were treated with either daily morphine (20 mg/kg, s.c.) alone, or in combination with simvastatin (2.5, 5 and 10mg/kg, i.p.), for 9 continuous days. Antinociceptive effect of morphine was assessed through measuring latency time withdrawal of paw exposed to thermal stimulus, in the hot plate test. Naloxone-precipitated morphine withdrawal (5mg/kg, i.p.), was used for dependence evaluation. Changes in brain gene expression levels of induced nitric oxide synthase (iNOS), astroglia marker, glial fibrillary acidic protein (GFAP), ionized calcium-binding protein (Iba1) a microglia activation marker, a pro-inflammatory mediator and tumor necrosis alpha (TNF-α) were measured after withdrawal by real-time polymerase chain reaction (RT-PCR). RESULTS: Behavioral tests indicated that latency time increased after morphine treatment in the hot plate test. However, this effect decreased on day 7, demonstrating tolerance to antinociceptive effect of morphine. Reduced anti-nociceptive effect of morphine was returned in animals treated with simvastatin (5 and 10mg/kg) in combination with morphine. Simvastatin (5 and 10mg/kg) attenuated morphine dependence as indicated by a less severe antagonist-precipitated withdrawal syndrome. Administration of naloxone was associated with the increased expression of TNF-α, GFAP, Iba1 and iNOS in the brain samples of morphine dependent mice, while the nine days treatment with both 5 and 10mg/kg simvastatin reduced such changes. CONCLUSION: The obtained results showed that the protective effects of simvastatin against both tolerance to nociceptive effects of morphine as well as withdrawal-induced behavioral profile are meaningful. Inhibition of glia activity as well as antioxidant effects of pharmaceutical simvastatin further proves its neuroprotective property.
Authors: Ryosuke Kojima; Daniel Bojar; Giorgio Rizzi; Ghislaine Charpin-El Hamri; Marie Daoud El-Baba; Pratik Saxena; Simon Ausländer; Kelly R Tan; Martin Fussenegger Journal: Nat Commun Date: 2018-04-03 Impact factor: 14.919