The effect of anandamide, a putative endogenous ligand of the cannabinoid receptor, has been studied in a naloxone-precipitated morphine withdrawal syndrome in mice. Animals were chronically treated with increasing doses of morphine (from 8 to 45 mg/kg) over 5 days or implanted with morphine pellets (72 hr). Typical signs of withdrawal (jumping and body weight loss) were examined after naloxone administration (1 mg/kg). In these conditions, anandamide (5 mg/kg, i.v.) decreased both the number of jumps, measured over 30 min (81.2% +/- 3.15 and 92.2% +/- 3.5 decrease in chronically administered morphine and pellet implanted mice, respectively), and the body weight loss at 30 and 60 min (30 min: 2.6% +/- 0.4 vs 4.4% +/- 0.2 and 3.7% +/- 0.4 vs 5.3% +/- 0.4; 60 min: 3.2% +/- 0.5 vs 5.0% +/- 0.4 and 4.1% +/- 0.5 vs 6.0% +/- 0.5 in chronically treated morphine and pellet implanted mice respectively) after naloxone administration. This suggests, as shown in the case of delta 9-tetrahydrocannabinol, a modulation by anandamide of pathways involved in the expression of physical signs of opioid dependence and support its role as an endogenous cannabinoid agonist.