Effects of 5-HT and alpha 1 adrenoceptor antagonists on kappa opioid-induced sedation

The kappa opioid agonists PD-117302 and U-50488 were found to produce dose-dependent reductions in spontaneous locomotor activity in mice. The magnitude of the response to a given dose of each kappa agonist was found to be clearly potentiated by pretreating the animals with either ketanserin (1 mg/kg) or prazosin (0.5 mg/kg). Pretreatment with the selective 5-HT2 receptor antagonist ritanserin given at a high dose (1 mg/kg), the nonselective 5-HT antagonist methysergide or the 5-HT synthesis inhibitor parachlorophenylalanine did not alter the magnitude of the response to the kappa agonist. These results suggest that 5-HT systems are not involved in the sedative effects of kappa opioid agonists and that the potentiating effect seen in animals pretreated with ketanserin is due to the alpha 1 blocking properties of this compound since the effect was mimicked by the alpha 1 antagonist prazosin.