An endogenous opiate mechanism may be involved in mediating the hypotensive effects of clonidine. In the cat anesthetized with alpha-chloralose, the effect of naloxone pretreatment on the lowering of blood pressure, heart rate and sympathetic nerve activity produced by increasing bolus i.c.v. injections of clonidine was studied. Central injections of clonidine (1-32 micrograms at 30-min intervals) decreased blood pressure, heart rate and renal nerve discharge in a dose-related manner. Effects on carotid sinus nerve activity were variable. Pretreatment with naloxone (3.2 mg x kg-1 i.v. or 1 mg i.c.v.) did not prevent the clonidine-induced reduction in blood pressure, heart rate and renal nerve activity. In some instances, the average blood pressure lowering responses to clonidine were greater in cats pretreated with naloxone compared with saline-pretreated animals. Changes in carotid sinus nerve activity were variable after clonidine in cats pretreated with i.v. naloxone. In contrast, sinus nerve activity decreased significantly after clonidine in cats pretreated with i.c.v. naloxone. Additional postclonidine naloxone injections (3.2 mg x kg-1 i.v. in all cats followed by 100 micrograms i.c.v. in the saline- and i.v. naloxone-pretreatment groups) also failed to consistently reverse the clonidine-induced changes in blood pressure, heart rate and sympathetic nerve activity. The results suggest that clonidine reduces blood pressure, heart rate and efferent sympathetic nerve firing in anesthetized normotensive cats by a mechanism independent of an opiate receptor interaction within the central nervous system.