Acetylcholine is an important neurotransmitter and neuromodulator in the brain. It mediates neural transmission in the ganglion synapses of both sympathetic and parasympathetic neurons, and is the principle neurotransmitter in the postganglionic parasympathetic/vagal efferent neurons. Acetylcholine acts through 2 types of receptors: muscarinic (metabotropic) (
70) and nicotinic (ionotropic) (
71). In addition to the brain and “wire-innervated” peripheral structures, the RNA for these receptor subtypes (muscarinic) and subunits (nicotinic) has been detected on mixed populations of lymphocytes and other immune and non-immune cytokine-producing cells (
72–
77). Most of these cells can also produce acetylcholine (
78).
We recently discovered that the α7 subunit of the nicotinic acetylcholine receptor is expressed on macrophages (
16). Acetylcholine significantly and concentration-dependently decreases TNF production by endotoxin-stimulated human macrophage cultures via a post-transcriptional mechanism. Using specific muscarinic and nicotinic agonists and antagonists, we demonstrated the importance of an α-bungarotoxin-sensitive nicotinic receptor in the inhibition of TNF synthesis in vitro by acetylcholine. Acetylcholine also is effective in suppressing other endotoxin-inducible pro-inflammatory cytokines, such as IL-1β, IL-6, and IL-18, by a post-transcriptional mechanism; release of the anti-inflammatory cytokine IL-10 from endotoxin-stimulated macrophages is not affected by acetylcholine (
16).
Because of the immunosuppressive effects of acetylcholine in vitro, we studied the possible immunonodulatory role of the parasympathetic division of the autonomic nervous system in vivo. In a rat model, vagotomy without electrical stimulation significantly increases serum and liver TNF levels in response to intravenously administered endotoxin (
Figure 2A and 2B), suggesting a direct role of efferent vagus neurons in the regulation of TNF production in vivo. Augmentation of efferent vagus nerve by direct electrical stimulation significantly attenuates endotoxin-induced serum and hepatic TNF (see
Figure 2A and 2B). TNF amplifies inflammation by activating the release of pro-inflammatory mediators such as IL-1, HMGB1, nitric oxide, and reactive oxygen species (
3,
6). TNF also plays an essential role in endotoxin-induced shock by inhibiting cardiac output, activating microvascular thrombosis, and modulating capillary leakage syndrome (
4,
79). These activities of TNF are consistent with the finding that attenuation of serum TNF via cervical vagus nerve stimulation prevents hypotension and shock in animals exposed to lethal doses of endotoxin (see
Figure 2C) (
16). Animals subjected to vagotomy without vagus nerve stimulation develop profound shock more quickly than sham-operated animals (see
Figure 2C), demonstrating a role for vagus nerve efferent signaling in maintaining immunological homeostasis. Importantly, the immunomodulatory effects of the efferent vagus nerve also play a role in localized peripheral inflammation, because electrical stimulation of the distal vagus nerve also inhibits the local inflammatory response in a standard rodent model of carrageenan-induced paw edema (
69). Pretreatment with acetylcholine, muscarine, or nicotine localized within the site of inflammation also prevents the development of hind paw swelling (
69). Vagal efferents are distributed throughout the reticuloendothelial system and other peripheral organs, and the brain-derived motor output through vagus efferent neurons is rapid. The cholinergic anti-inflammatory pathway is therefore uniquely positioned to modulate inflammation in real time.
, I've just realised I've been napping in the afternoons for the past few days. Don't know if that means anything. 
