Single-Pulse and Unidirectional Electrical Activation of the Cervical Vagus Nerve Reduces Tumor Necrosis Factor in Endotoxemia

Abstract

The inflammatory reflex is a neural circuit defined by action potentials transmitted in the vagus nerve that regulate cytokine production in the spleen. Detailed mechanistic studies implicate the vagus nerve, the splenic nerve, a T-cell subset that produces acetylcholine under the control of adrenergic signals, and alpha7 nicotinic acetylcholine receptors (α7nAChR). expressed on macrophages. This study defines the vagus nerve fibers that transmit the efferent signal in this pathway, a motor arc of the inflammatory reflex. Mice and rats were subjected to electrical cervical vagus nerve stimulation or sham surgery. Cytokine levels in serum were measured in endotoxemic animals or in endotoxin-exposed blood samples. Evoked potentials were measured in the vagus nerve and a portion of the vagus nerve was anesthetized using local application of lidocaine before stimulation. The lowest threshold subdiaphragmatic fibers in the rat vagus nerve have conduction velocities consistent with that of myelinated B fibers. The stimulation current threshold for significant suppression of serum TNF levels was similar in mice and rats (≤500 µA). Blockade of the fibers caudal to the site of vagus nerve stimulation impaired the inhibition of TNF release. A single suprathreshold pulse stimulation was sufficient to suppress TNF release in endotoxemia. These results indicate that single-pulse and unidirectional electrical activation of the cervical vagus nerve reduce TNF in endotoxemia.