Epidural clonidine depresses sympathetic nerve activity in humans by a supraspinal mechanism

Epidural administration of the alpha 2-adrenergic agonist clonidine induces hypotension. Animal experiments have indicated a possible spinal mechanism through activation of alpha 2-adrenergic receptors on sympathetic preganglionic neurons, resulting in a decrease of efferent sympathetic activity. However, the pharmacokinetic behavior of epidural clonidine, the high lipid solubility of the drug, and the apparent sedative side effects also indicate a possible supraspinal mechanism. To test this hypothesis, the effect of epidural and intramuscular clonidine on efferent sympathetic nerve activity to the leg was studied with microneurography. In 15 healthy volunteers, a lumbar epidural catheter was inserted and multiunit postganglionic sympathetic activity was recorded in a skin or muscle fascicle of the peroneal nerve before and after epidural injection of clonidine. Skin blood flow in the hand and in the foot was measured with laser Doppler flowmetry. In six additional experiments, performed at another time, clonidine was given intramuscularly. After epidural injection of clonidine (3 micrograms/kg) the resting level of skin sympathetic activity decreased to 18 +/- 5% (n = 6; P < 0.001), muscle sympathetic activity expressed as bursts/min to 41 +/- 12% (n = 7; P < 0.01), and integrated muscle sympathetic activity to 41 +/- 13% (n = 7; P < 0.01) of control values after 30 min. However, the capacity for activation of skin sympathetic activity by arousal stimuli and of muscle sympathetic activity by apnea remained. Intramuscular clonidine inhibited both skin sympathetic activity (n = 3) and muscle sympathetic activity (n = 3) to the same extent. Skin blood flow increased whereas blood pressure and heart rate decreased after epidural and intramuscular clonidine. The comparable inhibition of resting sympathetic nerve activity, paralleled by a decrease in heart rate and blood pressure after both epidural and intramuscular clonidine, indicates that epidural clonidine induces a supraspinally evoked general decrease in sympathetic outflow.