Evaluation of pentoxyphiline and natural honey on morphine-induced tolerance in male mice

Abstract

Introduction: Long-term use of opioids causes tolerance and dependency. The mechanisms of opioid tolerance are not fully understood but may involve oxidative stress, increase in inflammatory cytokines, glutamatergic system activation, inflammatory factors, and oxidative stress affect the opioid system. Pentoxyphiline is an anti-inflammatory drug and honey is a natural substance which has an antioxidant activity. Aim: The aim of this study was to evaluate the effect of Pentoxyphiline and honey IP-injection on morphine tolerance in male mice. Methods: Nine groups of male mice (n=8 in each group, weight=20-30 g) were administrated the following daily regimens for 4 days: 1. Saline (10 ml/kg,ip) + Saline (10 ml/kg,ip) 2. Saline (10 ml/kg,ip) + Morphine (50 mg/kg,ip) 3,4,5. Pentoxyphiline (20,30,60 mg/kg,ip) + Morphine (50 mg/kg,ip) 6,7,8. Honey (100,200,400 mg/kg,ip) + Morphine (50 mg/kg,ip) 9.Pentoxyphiline (20 mg/kg,ip) + Honey (100 mg/kg,ip) + Morphine (50 mg/kg,ip) In each group, the antinociceptive response of a test dose of morphine (9mg/kg,ip) was measured 24 hours after the last dose of morphine injection (50mg/kg,ip) by the hot-plate test, conducted within one hour, at minutes (15,30,45,60). Then blood sampling was performed. Plasma serums were provided and stored in -70℃ until TNF-α assays with relevant kits. Results: The result showed that administration of Pentoxyphiline )20,30,60 mg/kg,ip( and honey )100,200,400 mg/kg,ip( before daily injection of morphine, could not decrease morphine tolerance. Pentoxyphiline )20,30,60 mg/kg,ip( and honey )200,400mg/kg,ip) cause an decrease TNF-α in serum. Conclusion: Co-injection of pentoxyphiline and honey is better than just injecting one of them and was shown to reduce morphine tolerance.