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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.<\/jats:p>","DOI":"10.1073\/pnas.0600506103","type":"journal-article","created":{"date-parts":[[2006,3,20]],"date-time":"2006-03-20T20:44:26Z","timestamp":1142887466000},"page":"5219-5223","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":292,"title":["Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia"],"prefix":"10.1073","volume":"103","author":[{"given":"Valentin A.","family":"Pavlov","sequence":"first","affiliation":[{"name":"Laboratories of *Biomedical Science and"},{"name":"Center for Immunology and Inflammation, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahendar","family":"Ochani","sequence":"additional","affiliation":[{"name":"Laboratories of *Biomedical Science and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Gallowitsch-Puerta","sequence":"additional","affiliation":[{"name":"Laboratories of *Biomedical Science and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanta","family":"Ochani","sequence":"additional","affiliation":[{"name":"Laboratories of *Biomedical Science and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared M.","family":"Huston","sequence":"additional","affiliation":[{"name":"Laboratories of *Biomedical Science and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Czura","sequence":"additional","affiliation":[{"name":"Laboratories of *Biomedical Science and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Al-Abed","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry,"},{"name":"Center for Immunology and Inflammation, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Tracey","sequence":"additional","affiliation":[{"name":"Merinoff Center for Patient Oriented Research, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,3,20]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01321"},{"key":"e_1_3_3_2_2","first-page":"128","volume-title":"Fatal Sequence: The Killer Within","author":"Tracey K. 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