Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia.

Abstract

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.

• Authors: Valentin A Pavlov, Mahendar Ochani, Margot Gallowitsch-Puerta, Kanta Ochani, Jared M Huston, Christopher J Czura, Yousef Al-Abed, Kevin J Tracey
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 13 Pg. 5219-23 (Mar 28 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16549778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Diamines
• Muscarinic Agonists
• Receptors, Muscarinic
• Tumor Necrosis Factor-alpha
• methoctramine

Topics

• Animals
• Brain (drug effects, metabolism)
• Diamines (administration & dosage, pharmacology)
• Endotoxemia (chemically induced, metabolism)
• Heart Rate (drug effects)
• Inflammation (metabolism)
• Male
• Muscarinic Agonists (pharmacology)
• Rats
• Receptors, Muscarinic (metabolism)
• Systemic Inflammatory Response Syndrome (chemically induced, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)