Study of the mechanisms involved in behavioral changes induced by flunitrazepam in morphine withdrawal

1. The attenuation of morphine withdrawal syndrome by acute benzodiazepine administration has been well documented. However, the pharmacological mechanisms implicated in this effect remain unclear. 2. In this study, the possible participation of noradrenergic, serotonergic and benzodiazepine receptors on flunitrazepam-modified morphine withdrawal syndrome was investigated in mice. Flunitrazepam was associated to the noradrenergic antagonists prazosin (1 mg/kg) and propranolol (0.5 mg/kg), the serotonergic agents ritanserine (1 mg/kg) and p-chloro phenylalanine (600 mg/kg), the benzodiazepine antagonist flumazenil (10 mg/kg), and the benzodiazepine partial inverse agonist Ro 15-4513 (5 mg/kg). 3. The decrease in jumping behavior-induced by flunitrazepam was potentiated by prazosin, while ritanserine, flumazenil and Ro 15-4513 blocked this effect. 4. Flunitrazepam-induced increase on wet dog shake frequency was partially reduced by flumazenil, and strongly antagonized by ritanserine and Ro 15-4513. 5. Noradrenergic and serotonergic systems seem to be primarily implicated in the changes induced on jumping and wet dog shakes respectively. These modifications are induced through the activation of the benzodiazepine receptors.