The role of Neurogenic inflammation in Pathophysiology of Fibromyalgia

The role of Neurogenic inflammation in Pathophysiology of Fibromyalgia

Inflammation is a part of the process of healing the body. Without healing there will be no treatment for diseases and wounds. But inflammation can potentially be harmful, too. There are two forms of, acute and chronic inflammation. Acute inflammation from an injury or infection comes on suddenly. It has classic symptoms like swelling , redness and pain.

Acute inflammation is momentary and lasts from a few days to a few weeks, depending on the source of the inflammation. Chronic inflammation is an infection that lasts for months and years on end. Slowly it comes about and sets the stage for chronic illnesses. A chronic inflammation is associated with heart disease, autoimmune diseases , neurological diseases, diabetes , cancer, Alzheimer’s, arthritis and many other conditions.

Fibromyalgia, a central sensitivity syndrome

Fibromyalgia is considered one of the syndromes with the central sensitivity. There is increasing evidence of inflammatory mechanisms neurogenically derived that occur in fibromyalgia in the peripheral tissues, spinal cord and brain. These include a variety of neuropeptides, chemokines, and cytokines with both innate and adaptive immune system activation.

This cycle results in some of the clinical peripheral manifestations of fibromyalgia, such as swelling and dysesthesia, and can affect central symptoms , such as fatigue and cognitive changes. In turn, physiological mechanisms related to emotions and stress are seen as the upstream drivers of neurogenic inflammation in fibromyalgia.

Fibromyalgia is a chronic pain condition of strong effects, with a well-defined and robust clinical phenotype. Widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress are key features. Abnormal pain and other sensory input processing occurs in the brain , spinal cord and periphery and is related to central and peripheral sensitisation processes.

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Neurogenic inflammation

Neurogenic inflammatory processes have long been involved in the pathophysiology of various human nervous system diseases , respiratory system, gastrointestinal tract, urogenital tract and skin as a possible mechanism. The recent creation of many groundbreaking experimental migraine models has provided preliminary proof of neuropeptide involvement (SP, neurokininin A, and CGRP) in migraine headache.

Neurogenic inflammation, a well-defined pathophysiological process, is characterized by the release from activated peripheral nociceptive sensory nerve terminals (usually C and A delta fibers) of potent vasoactive neuropeptides, predominantly calcitonin-related peptide (CGRP), substance P (SP), and neurokinin A. These peptides lead to a cascade of inflammatory tissue responses including arteriolar vasodilatation, extravasation of plasma proteins, and mast cell degranulation in their peripheral target tissue. In a rat study, deficiency of magnesium induces neurogenic inflammation.

Scientists have theorized that since substance P, which occurs on day five of induced magnesium deficiency, is known to in effect trigger the development of other inflammatory cytokines, including IL-1, Interleukin 6 (IL-6), and TNF-alpha (TNFα), which begin a steep increase on day 12, substance P is a key in the progression from magnesium deficiency to the resulting neuroinflammatory cascade.

Pathophysiology of pain

Neuropathic pain is caused in the peripheral and central nervous system by inflammatory processes within nerve cells and fibers. Pathophysiology may be associated with compression (such as in carpal tunnel syndrome or vertebral disk herniation) or nerve regeneration, resulting in ectopic impulse discharges and axonal transport disturbances. In fibromyalgia, the resulting neuronal hyperexcitability and trophic changes induced by a disturbed axonal transport system can be major pain factors.

Dysregulatory pain signifies pain caused by efferent control system dysfunction. Thus, if the spinal motoneuron production results in unnecessary postural muscle stress, nociceptors can become more agitated in muscles, tendons , and joints. Fibromyalgia-related pain may consist of a complex interaction of psychosomatic mechanisms and nociceptive, neuropathic, dysregulatory central nervous system.

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Nociceptor pain is based on the excitation of specialized nervous sensors to signal potentially harmful stimuli, i.e. the nociceptors. Metabolic deficits in muscle and neurogenic inflammation induced by the release of substance P and other neuropeptides from the peripheral nerve endings may contribute to chemical sensitization of nociceptors and consequent hyperalgesia especially present in tender points.

Psychological trauma may be the cause of fibromyalgia

While there are distinct clinical phenotypes for fibromyalgia and complex regional pain syndrome (CRPS), they both share certain common characteristics. In each condition, pain, allodynia, and dysaesthesia occur and appear to exist on a similar spectrum. Both fibromyalgia and CRPS can be triggered by specific traumatic events, although fibromyalgia is most commonly associated with psychological trauma, and CRPS is most frequently associated with physical trauma, which the patient frequently deems routine or minor.

Fibromyalgia and CRPS both tend to have many pathophysiological pathways, the most important of which are those that cause core effects. Nonetheless, peripheral effects such as neurogenic neuroinflammation also contribute significantly to the clinical characteristics of each of these disorders.

Treatment

Botulinum toxin has been shown to have an effect on neurogenic inflammation inhibitors, and data suggests the role of neurogenic inflammation in psoriasis pathogenesis. Statins tend to “decrease the expression of the gene-related proinflammatory neuropeptides calcitonin peptide and substance P in sensory neurons, and therefore could be beneficial in treating diseases of prevalent neurogenic inflammation.

Astelin (Azelastine) “is recommended in adults and children aged 12 years and older for symptomatic treatment of vasomotor rhinitis involving rhinorrhea, nasal inflammation, and postnasal leak.

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Neurophysiologic factors in fibromyalgia

There was also a better understanding of the influence of social and psychological factors on fibromyalgia, particularly those related to the reactivity of the stress response on core neural systems related to pain. In this dynamic combination of different influencing factors, researchers have been cautious to classify observable neurophysiological causes. Much of this took time. However, current fibromyalgia research in other chronic pain conditions is aligned with cutting edge research. Fibromyalgia is not a satisfactory animal model.

Peripheral neural stimulation

A minority of researchers feel the sensitivity of the pain-related nervous system in fibromyalgia has to do with peripheral neural stimulation that primes the process of sensitization. This is based on traditional neurophysiological research , especially in animals, where the pain response is initiated by peripheral stimulation.

I believe that more researchers feel that the brain and spinal cord play a major role in modulating peripheral sensory inputs, and when the neurons of the spinal cord are sensitized by a change in brain modulation, various otherwise non-painful stimuli may access the pain-related nervous system and cause fibromyalgia pain. The mechanisms behind such effects are still to be fully identified.

References:

  • The Role of Neurogenic Inflammation in Fibromyalgia Pathophysiology by Cindy Lampner, MSLIS via Rheumatology Advisor
  • Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation – the peripheral nervous system’s role in host defense and immunopathology. Nat Neurosci. 2012;15:1063-1067.
  • Littlejohn G, Guymer E. Neurogenic inflammation in fibromyalgia. Semin Immunopathol. 2018;40:291-300.

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