Effects of glucosamine against morphine-induced antinociceptive tolerance and dependence in mice

BackgroundThe most important limitations of morphine in pain therapy are its tolerance and dependence. In this study, we evaluated the protective effect of glucosamine against morphine-induced tolerance and dependence in mice.MethodsMice received twice daily morphine (20mg/kg, s.c.) alone, or along with orally administered glucosamine (500, 1000 and 2000mg/kg), for 9 continuous days. To assess antinociceptive effect of morphine, percentage of maximal possible effect (%MPE) of animals exposed to thermal stimulus was measured in the hot plate test, 30min after morphine administration. Test was performed on days 1, 3, 5, 7 and 9. The effect of glucosamine on the naloxone (5mg/kg, i.p.)-precipitated morphine withdrawal, was also evaluated. Changes in brain gene expression levels of induced nitric oxide synthase (iNOS), enzyme responsible for nitric oxide generation, as well as pro-inflammatory mediator, tumor necrosis alpha (TNF-) were measured in morphine tolerated animals, as well as after withdrawal by real-time polymerase chain reaction (RT-PCR). Protein content of TNF- was evaluated via ELISA assay.ResultsTolerance to antinociceptive effect of morphine was developed after 7days of morphine treatment. The concurrent administration of glucosamine (500, 1000 and 2000mg/kg) with morphine, significantly inhibited tolerance development, on days 7 and 9. In addition, glucosamine ameliorated the naloxone-precipitated opioid withdrawal symptoms (tremor, jumping, teeth chattering, grooming). However, diarrhea was significantly improved only with the dose of 500mg/kg. Increased mRNA expression of iNOS as well as TNF- mRNA expression and protein, after both morphine tolerance and withdrawal, were considerably reduced by glucosamine (1000mg/kg) in the morphine withdrawal animals.ConclusionThese data support the utility of glucosamine in attenuating both tolerance to nociceptive effects of morphine as well as withdrawal-induced behavioral profile. Anti-oxidant and anti-inflammatory effects are responsible, at least in part, for the protective effects of this drug.