Intravenous injection of clonidine produces a biphasic blood pressure response, a transient increase followed by a prolonged decrease. Significant increases in plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) levels occur 5 min following injection, corresponding to the hypertensive phase. Thirty minutes after clonidine injection, blood pressure, NE, EPI, and DA levels had returned to control levels. However, at 60 min, when the blood pressure had decreased to below control levels, a significant decrease in plasma NE was found. This finding confirms that clonidine decreases blood pressure, in part, by reducing sympathetic nerve activity. Naloxone, an opiate antagonist, when given prior to clonidine, abolished the hypotensive phase as well as preventing the decrease in plasma NE levels. The hypertensive phase was potentiated. Naloxone, when given alone, increased plasma NE levels at 15, 40, and 70 min following injection, indicating that naloxone increases sympathetic nerve activity peripherally, and may prevent clonidine's hypotensive phase by also increasing sympathetic activity in the central nervous system through blockade of opiate receptors. Therefore, the hypotensive effect of clonidine may involve interactions with endogenous opiate peptides.