Pavlov VA; Ochani M; Gallowitsch-Puerta M;
Ochani K; Huston JM; Czura CJ;
Al-Abed Y; Tracey KJ
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research,
350 Community Drive, Manhasset, NY 11030, USA. vpavlov@nshs.edu
TNF has a critical mediator role
in inflammation and is an important therapeutic target. We recently discovered
that TNF production is regulated by neural signals through the vagus nerve. Activation of this "cholinergic antiinflammatory pathway" inhibits the production of
TNF and other cytokines and protects animals from the inflammatory damage
caused by endotoxemia and severe sepsis. Here, we describe
a role for central muscarinic acetylcholine receptors in the activation of the
cholinergic antiinflammatory pathway. Central
muscarinic cholinergic activation by muscarine, the
M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly
during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve
activity measured by changes in instantaneous heart-rate variability. Blockade
of peripheral muscarinic receptors did not abolish antiinflammatory
signaling through the vagus nerve, indicating that
peripheral muscarinic receptors on immune cells are not required for the
cytokine-regulating activities of the cholinergic antiinflammatory
pathway. The role of central muscarinic receptors in activating the cholinergic
antiinflammatory pathway is of interest for the use
of centrally acting muscarinic cholinergic enhancers as antiinflammatory
agents.