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The vagus nerve and the nicotinic anti-inflammatory pathway

Nature Reviews Drug Discovery volume 4, pages 673–684 (2005)Cite this article

Key Points

  • Inflammation is a fundamental physiological process that is crucial for survival, but at the same time it is one of the major causes of human morbidity and mortality. The production of pro-inflammatory cytokines is beneficial and protects the organism against infections and injury. However, excessive production of these cytokines can be more dangerous than the original infection, resulting in lethal systemic inflammation. These cytokines are successful pharmacological targets for the treatment of a variety of clinical disorders.

  • Severe sepsis, the leading cause of death in intensive care units, is one of the most dramatic examples of the pathological potential of inflammation is sepsis. Severe sepsis is the third leading cause of death in developed societies, equals the number of fatalities from acute myocardial infarction, and accounts for 9.3% of overall deaths in the United States annually.

  • Vagus-nerve stimulation, acetylcholine and nicotine inhibit the production of pro-inflammatory cytokines from macrophages through a 'nicotinic anti-inflammatory pathway' that is dependent on the α7 nicotinic acetylcholine receptor (α7nAChR).

  • Similar to the development of α- and β-agonists for adrenergic receptors, the design of selective nicotinic agonists for the α(α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.

  • The therapeutic potential of nicotinic agonists has been limited by the characterization of the specific receptors for drug development. The recent characterization of the α7nAChR in macrophages supports the design of selective nicotine agonists that can overcome the toxic effect of nicotine mediated by other receptors.

Abstract

Physiological anti-inflammatory mechanisms are selected by evolution to effectively control the immune system and can be exploited for the treatment of inflammatory disorders. Recent studies indicate that the vagus nerve (which is the longest of the cranial nerves and innervates most of the peripheral organs) can modulate the immune response and control inflammation through a 'nicotinic anti-inflammatory pathway' dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Nicotine has been used in clinical trials for the treatment of ulcerative colitis, but its clinical applications are limited by its unspecific effects and subsequent toxicity. This article reviews recent advances supporting the therapeutic potential of selective nicotinic agonists in several diseases. Similar to the development of α- and β-agonists for adrenoceptors, selective agonists for α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.

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Figure 1: Inflammation contributes to the pathological progression of a variety of disorders.
Figure 2: Pharmacological activator of the vagus nerve.
Figure 3: The 'nicotinic anti-inflammatory pathway'.
Figure 4: Chemical structure of selective cholinergic agonists and antagonists.
Figure 5: Human nicotinic acetylcholine subunits.
Figure 6: Nicotinic regulation of pro-inflammatory cytokines.
Figure 7: Clinical implications of the vagus nerve and the 'nicotinic anti-inflammatory pathway'.

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Acknowledgements

The author is supported by the Faculty Award Program of the North Shore Health System and the North Shore-LIJ GCRC. The author is grateful for the critical reading and thoughtful suggestions from K. J. Tracey, E.Tuomanen. E. J. Miller, P. Morcillo, and P. Wang.

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  1. Center of Immunology and Inflammation, Institute for Medical Research, North Shore University Hospital, 350 Community Drive, New York, 11030, USA

    Luis Ulloa

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DATABASES

Entrez Gene

α7nAChR

α-MSH

ACTH

HMGB1

IL-1

TNF

OMIM

Ankylosing spondylitis

Chrohn's disease

depression

Parkinson's disease

psoriasis

rheumatoid arthritis

Tourette's syndrome

ulcerative colitis

FURTHER INFORMATION

Chemistry Of Drugs And The Brain

Cholinomimetic Drugs

Neuronal Nicotinic Receptors

Pharmacological Research University of Toledo

Glossary

SEPSIS

The clinical signs of a systemic inflammatory response to infection; 'severe sepsis' refers to organ dysfunction observed during systemic inflammation even in the absence of confirmed infection.

SHOCK

Bodily collapse or near collapse caused by inadequate oxygen delivery to the cells; characterized by reduced cardiac output, rapid heartbeat, circulatory insufficiency and pallor. Loss of blood is an important cause of shock.

ISCHAEMIA

A decrease in the blood supply to a bodily organ, tissue or body part caused by constriction or obstruction of the blood vessels.

ACETYLCHOLINE

A crystalline derivative of choline that is released at the ends of nerve fibres in the somatic and parasympathetic nervous systems and is involved in the transmission of nerve impulses in the body.

NICOTINIC ACETYLECHOLINE RECEPTORS

One of the two classes of cholinergic receptors. Nicotinic receptors are defined by their preference for binding nicotine over muscarine.

NICOTINIC AGONISTS

Chemical analogues of nicotine that can bind to a specific subset of nicotine acetylcholine receptors.

ENDOTOXIN

A toxin produced by Gram-negative bacteria and released from the bacterial cell.

VAGOTOMY

Surgical sectioning of fibres of the vagus nerve, previously used to diminish acid secretion of the stomach and control a duodenal ulcer.

MUSCARINIC RECEPTORS

One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for muscarine over nicotine.

MUSCARINE

A highly toxic alkaloid related to the cholines, derived from the red form of the mushroom Amanita muscaria and found in decaying animal tissue.

ALLODYNIA

Pain originating from a non-injurious stimulus to the skin.

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Ulloa, L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4, 673–684 (2005). https://doi.org/10.1038/nrd1797

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