Evaluation of the effects of meloxicam and crocin in dependency induced by morphine in 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. Meloxicam, is an anti-inflammatory drug and crocin (saffron extract) as a herbal agent have antioxidant activity. Aim: The aim of the present study was to investigate the effects of meloxicam and crocin in the prevention of morphine induced dependence in mice. Materials and methods:Ten groups containing 9 male mice in weight group 20-30 gr were randomly selected and received the regimens mentioned below once daily for 4 days. The group recieved Saline + Saline ,Saline + Morphine ,DMSO 25% + Morphine , Three different doses of Crocin (100,200,400 mg/kg , i.p) + Morphine ,Three different doses of Meloxicam (5,10,20mg/kg , i.p) + Morphine , Crocin (100mg/kg , i.p) + Meloxicam (5mg/kg , i.p) + Morphine. To investigate the effect of drugs on morphine dependency on day 4th, 2 hours after the last dose of morphine injection, naloxane was injected and symptoms of withdrawal syndrome (number of jumping and standing on feet) was recorded within half an hour in each mice. Eventually to evaluate the effect of these drugs on pro-inflammatory cytokines, blood samples from the heart of the animals were taken and tests for TNF-α were performed. Results: The result showed that administration of meloxicam (20 mg/kg , i.p) and crocin(100,400 mg/kg , i.p) before daily injection of morphine , decrease morphine dependency. Meloxicam causes an increase in serum TNF-α and crocin(100, 200, 400 mg/kg , i.p) decrease TNF-α in serum. Conclusion: Based on these findings, meloxicam (20 mg/kg , i.p) and crocin (100,400 mg/kg , i.p) along with morphine may be helpful in reducing morphine dependency, when chronic opioid use is required. Part of the effects of crocin administration in reducing withdrawal symptoms may be related to inhibition of TNF-α production.