Cholinergic Pathways, the Immune System and Arthritis
Cholinergic Pathways, the Immune System and Arthritis
Around the turn of the century Borovikova and colleagues, working in the Tracey laboratory, showed that an anti-inflammatory drug, CNI-1493, was effective in suppressing both local inflammation (carrageenan-induced paw oedema) and systemic inflammation (hypotension and the inflammatory cytokine response to intravenous treatment with lipopolysaccharide (LPS)) in anaesthetised rodents - the strength of a systemic inflammatory response to a stimulus such as LPS is often measured by the levels of the pro-inflammatory cytokine, tumour necrosis factor (TNF). These workers found that CNI-1493 was many times more potent in suppressing inflammation when given into the cerebral ventricles than when given intravenously, showing that its site of action was in the central nervous system. Later, it was found to act via central muscarinic receptors, and that other muscarinic agonists with central neural actions had similar anti-inflammatory effects. Furthermore, treatment with the centrally acting cholinesterase inhibitor, galantamine, was found to suppress acute systemic inflammation. This last finding suggests that central cholinergic neurons (Figure 1) tonically release acetylcholine close to the muscarinic receptors that drive the anti-inflammatory action.
The output pathway stimulated by these central muscarinic actions was found to run in the vagus nerves (discussed below). The anti-inflammatory action of these muscarinic agonists was blocked by centrally acting muscarinic antagonists but not by atropine methyl nitrate, which does not cross the blood–brain barrier. These observations are in line with those of others who concluded that central but not peripheral muscarinic receptors have an anti-inflammatory action.
Muscarinic receptors in the spinal cord have also been shown to exert anti-inflammatory actions. Yoon and colleagues found that intrathecal injection of a muscarinic M2 receptor agonist suppressed peripheral inflammation in the zymosan-treated air pouch model in mice. In this case, however, the anti-inflammatory action was mediated by sympathetic nerves to the adrenal medulla and the release of adrenal catecholamines.
Central Neural Cholinergic Pathways
Around the turn of the century Borovikova and colleagues, working in the Tracey laboratory, showed that an anti-inflammatory drug, CNI-1493, was effective in suppressing both local inflammation (carrageenan-induced paw oedema) and systemic inflammation (hypotension and the inflammatory cytokine response to intravenous treatment with lipopolysaccharide (LPS)) in anaesthetised rodents - the strength of a systemic inflammatory response to a stimulus such as LPS is often measured by the levels of the pro-inflammatory cytokine, tumour necrosis factor (TNF). These workers found that CNI-1493 was many times more potent in suppressing inflammation when given into the cerebral ventricles than when given intravenously, showing that its site of action was in the central nervous system. Later, it was found to act via central muscarinic receptors, and that other muscarinic agonists with central neural actions had similar anti-inflammatory effects. Furthermore, treatment with the centrally acting cholinesterase inhibitor, galantamine, was found to suppress acute systemic inflammation. This last finding suggests that central cholinergic neurons (Figure 1) tonically release acetylcholine close to the muscarinic receptors that drive the anti-inflammatory action.
The output pathway stimulated by these central muscarinic actions was found to run in the vagus nerves (discussed below). The anti-inflammatory action of these muscarinic agonists was blocked by centrally acting muscarinic antagonists but not by atropine methyl nitrate, which does not cross the blood–brain barrier. These observations are in line with those of others who concluded that central but not peripheral muscarinic receptors have an anti-inflammatory action.
Muscarinic receptors in the spinal cord have also been shown to exert anti-inflammatory actions. Yoon and colleagues found that intrathecal injection of a muscarinic M2 receptor agonist suppressed peripheral inflammation in the zymosan-treated air pouch model in mice. In this case, however, the anti-inflammatory action was mediated by sympathetic nerves to the adrenal medulla and the release of adrenal catecholamines.