In opioid addicted patients, respiratory regulation adapts allowing intake of otherwise lethal dosages of opioids. In contrast, little is known about cardiovascular regulation during chronic opioid receptor stimulation. We previously demonstrated that chronic mu-opioid receptor stimulation by methadone decreases resting muscle sympathetic activity (MSA). However, for short-term control of arterial blood pressure autonomic responses to arterial hypotension may be of greater importance. Accordingly, we tested the hypothesis that chronic opioid receptor stimulation attenuates muscle sympathetic and heart rate responses to arterial hypotension. Ten young patients (mean +/- SD, 30 years +/- 6) with a long history of mono-opioid addiction and under oral methadone substitution therapy (54 mg d(-1) +/- 31) for 12 months (+/-20) were studied. Peroneal MSA (microneurography) and heart rate responses to hypotensive challenges (sodium nitroprusside) were assessed in the awake state and compared with those of 10 matched healthy subjects. Effects of mu-opioid receptor blockade by naloxone (12.4 mg i.v.) were determined during propofol anesthesia. Chronic mu-opioid receptor stimulation markedly decreased the MSA response to hypotension (-0.5 units mm Hg(-1) +/- 0.2 vs. -2.0 +/- 1.8; p = 0.01) compared with healthy subjects despite similar arterial blood pressure and heart rate at rest. In contrast, the heart rate response to hypotension did not differ between addicted patients (6 ms mm Hg(-1) +/- 2) and healthy subjects (7 ms mm Hg(-1) +/-4). Opioid receptor blockade during propofol anesthesia markedly increased the MSA response to hypotension even beyond awake values (-1.2 units mm Hg(-1) +/- 1.1; p = 0.02 vs. awake) while the heart rate response remained unchanged. Thus, chronic mu-opioid receptor stimulation 1) results in uncompensated depression of cardiovascular sympathetic neural regulation, and 2) exerts differential effects on efferent sympathetic nerve activity to muscle and on heart rate control in response to arterial hypotension.