Neurogenic inflammation is

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

arising from the local release by

afferent neurons Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The cel ...

of inflammatory mediators such as

Substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clos ...

, Calcitonin Gene-Related Peptide (CGRP),

neurokinin A Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflam ...

(NKA), and

endothelin-3 Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

(ET-3). In such neurons, release of these pro-inflammatory mediators is thought to be triggered by the activation of ion channels that are the principal detectors of noxious environmental stimuli. In particular, the heat/capsaicin receptor TRPV1 and the irritant/wasabi receptor TRPA1.

TRPA1 Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the ''TRPA1'' (and in mice and rats by the ''Trpa1' ...

channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. Neurogenic inflammation appears to play an important role in the

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of numerous diseases including

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

, vasomotor rhinitis,

fibromyalgia Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...

eczema Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...

rosacea Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, enlarge ...

dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...

, and

multiple chemical sensitivity Multiple chemical sensitivity (MCS), also known as idiopathic environmental intolerances (IEI), is an unrecognized and controversial diagnosis characterized by chronic symptoms attributed to exposure to low levels of commonly used chemicals. Symp ...

. In

, stimulation of the

trigeminal nerve In neuroanatomy, the trigeminal nerve ( lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for sensation in the face and motor functions such as biting and chewin ...

causes neurogenic inflammation via release of neuropeptides including

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

vasoactive intestinal polypeptide Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligan ...

, 5-HT,

Neurokinin A Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflam ...

and

CGRP Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 ( intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produc ...

. leading to a "sterile neurogenic inflammation."

Prevention

Magnesium deficiency Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and ...

causes neurogenic inflammation in a rat model. Researchers have theorized that since

substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clos ...

which appears at day five of induced magnesium deficiency, is known to stimulate in turn the production of other inflammatory cytokines including IL-1, Interleukin 6 (IL-6), and TNF-alpha (TNFα), which begin a sharp rise at day 12, substance P is a key in the path from magnesium deficiency to the subsequent cascade of neuro-inflammation. In a later study, researchers provided rats dietary levels of magnesium that were reduced but still within the range of dietary intake found in the human population, and observed an increase in

, TNF alpha (TNFα) and Interleukin-1 beta (IL-1β), followed by exacerbated bone loss. These and other data suggest that deficient dietary

magnesium Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ta ...

intake, even at levels not uncommon in humans, may trigger neurogenic inflammation and lead to an increased risk of

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

Treatment

In 2018, three CGRP blockers were approved by the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for the prevention of migraine: erenumab; fremanezumab; and galcanezumab. :The calcitonin gene-related peptide (CGRP) is a therapeutic target in migraine because of its hypothesized role in mediating trigeminovascular pain transmission and the vasodilatory component of neurogenic inflammation (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Role of calcitonin gene-related peptide'). In 2018, the US Food and Drug Administration (FDA) approved the CGRP antagonists erenumab 6 fremanezumab 7 and galcanezumab 8for migraine prevention. :Smith, "Preventive treatment of migraine in adults" UpToDate 2019 Additional CGRP blockers are progressing through clinical trials. Anticipating later

botox Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neurom ...

therapy for migraine, early work by Jancsó ''et al.'' found some success in treatment using denervation or pretreatment with

capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...

to prevent uncomfortable symptoms of neurogenic inflammation. A 2010 study of the treatment of migraine with

blockers had shown promise for CGRP blockers. In early trials, the first oral nonpeptide

antagonist, MK-0974 (

Telcagepant Telcagepant (INN) (code name MK-0974) is a calcitonin gene-related peptide receptor antagonist which was an investigational drug for the acute treatment and prevention of migraine, developed by Merck & Co. In the acute treatment of migraine, ...

), was shown effective in the treatment of migraine attacks, but elevated liver enzymes in two participants were found. Other therapies and other links in the neurogenic inflammatory pathway for interruption of disease are under study, including

therapies. Noting that

botulinum toxin Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromusc ...

has been shown to have an effect on inhibiting neurogenic inflammation, and evidence suggesting the role of neurogenic inflammation in the

, the

University of Minnesota The University of Minnesota, formally the University of Minnesota, Twin Cities, (UMN Twin Cities, the U of M, or Minnesota) is a public university, public Land-grant university, land-grant research university in the Minneapolis–Saint Paul, Tw ...

has a pilot

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

underway to follow up on the observation that patients treated with botulinum toxin for

had dramatic improvement in psoriasis. Astelin ( Azelastine) "is indicated for symptomatic treatment of

vasomotor rhinitis Nonallergic rhinitis is rhinitis—inflammation of the inner part of the nose—not caused by an allergy. Nonallergic rhinitis displays symptoms including chronic sneezing or having a congested, drippy nose, without an identified allergic reaction ...

including

rhinorrhea Rhinorrhea, rhinorrhoea, or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is a common condition. It is a common symptom of allergies ( hay fever) or certain viral infections, such as the common cold or COVID- ...

, nasal congestion, and post nasal drip in adults and children 12 years of age and older."

Statins Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...

appear to "decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons," and so might be of use in treating diseases presenting with predominant neurogenic inflammation.

Research

In a 2012 article in ''Nature Neuroscience'' Chiu ''et al.'' discuss the development of science related to neurogenic inflammation and provide a graphicFig. 3 of article
illustrating key discoveries leading toward the current understanding of neurogenic inflammation, its mechanisms, and the conditions caused by its disorder.

References

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External links

* Schön and Boehncke, ttp://content.nejm.org/cgi/content/full/352/18/1899 Psoriasis: Neurogenic inflammation and other mechanismsNEJM 352:1899–1912, Number 18, 2005 Inflammations