Changes in benzodiazepine-receptor activity modify morphine withdrawal syndrome in mice

The effects of different benzodiazepine-receptor ligands on morphine withdrawal were studied: a benzodiazepine agonist, flunitrazepam; a benzodiazepine antagonist, flumazenil; a partial inverse benzodiazepine agonist, Ro 15-4513; and a partial benzodiazepine agonist, Ro 16-6028. Benzodiazepine-ligands were administered i.p. 30 min before naloxone-induced morphine withdrawal syndrome. Jumping behavior was significantly increased by Ro 15-4513 at 10 and 20 mg/kg. Flunitrazepam decreased jumps at all the doses used. Wet dog shakes were decreased by flumazenil and Ro 15-4513 and increased by Ro 16-6028 (only at the highest dose) and flunitrazepam. Our results show that the activation of the benzodiazepine receptor by agonists or high doses of partial agonists decreases jumping and increases wet dog shake behaviour, while the antagonists or the partial inverse agonists enhance jumping and decrease wet dog shakes. These modifications could be interpreted as an attenuation in the severity of the morphine withdrawal syndrome by benzodiazepine agonists.