The Role of Neurogenic Inflammation in Fibromyalgia Pathophysiology

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Inflammation is part of the body’s healing process. Without inflammation, infections and wounds would not heal. But inflammation can also be potentially harmful. There are two types of inflammation, acute and chronic. Acute inflammation comes on suddenly from an injury or infection. It presents classic symptoms such as swelling, redness and pain.

Acute inflammation is momentary, lasting from a few days to a couple of weeks, depending on the origin of the inflammation. Chronic inflammation is long-term inflammation that lasts for months and years. It comes about slowly and sets the stage for chronic diseases. Heart disease, autoimmune diseases, neurological diseases, diabetes, cancer, Alzheimer’s, arthritis and many other conditions are linked to chronic inflammation.

Fibromyalgia, a central sensitivity syndrome

Fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems.

This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization.

Neurogenic inflammation

Neurogenic inflammatory processes have long been implicated as a possible mechanism involved in the pathophysiology of various human diseases of the nervous system, respiratory system, gastrointestinal tract, urogenital tract, and skin. The recent development of several innovative experimental migraine models has provided evidence suggestive of the involvement of neuropeptides (SP, neurokinin A, and CGRP) in migraine headache.

Neurogenic inflammation, a well-defined pathophysiologial process is characterized by the release of potent vasoactive neuropeptides, predominantly calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A from activated peripheral nociceptive sensory nerve terminals (usually C and A delta-fibers). These peptides lead to a cascade of inflammatory tissue responses including arteriolar vasodilation, plasma protein extravasation, and degranulation of mast cells in their peripheral target tissue. Magnesium deficiency causes neurogenic inflammation in a rat model.

Researchers have theorized that since substance P 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.

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Pathophysiology of pain

Neuropathic pain is due to pathological mechanisms within nerve cells and fibers in the peripheral and central nervous system. Pathophysiology may be related to compression (such as in the carpal tunnel syndrome or a vertebral disk herniation) or regeneration of nerves, resulting in ectopic impulse discharges and disturbances of axonal transport. The ensuing neuronal hyperexcitability and trophic changes induced by a disturbed axonal transport system may be major factors of pain in fibromyalgia.

Dysregulatory pain denotes pain maintained by dysfunction of efferent control loops. Thus, if spinal motoneuron output results in excessive tension of postural muscle, nociceptors in muscles, tendons and joints might become more excited. Pain related to fibromyalgia may consist of a complex interaction of nociceptive, neuropathic, dysregulatory central nervous system and psychosomatic mechanisms.

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

Psychological trauma may be the cause of fibromyalgia

Although fibromyalgia and complex regional pain syndrome (CRPS) have distinct clinical phenotypes, they do share many other features. Pain, allodynia and dysaesthesia occur in each condition and seem to exist on a similar spectrum. Fibromyalgia and CRPS can both be triggered by specific traumatic events, although fibromyalgia is most commonly associated with psychological trauma and CRPS is most often associated with physical trauma, which is frequently deemed routine or minor by the patient.

Fibromyalgia and CRPS also seem to share many pathophysiological mechanisms, among which the most important are those involving central effects. Nonetheless, peripheral effects, such as neurogenic neuroinflammation, are also important contributors to the clinical features of each of these disorders.

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Treatment

Botulinum toxin has been shown to have an effect on inhibiting neurogenic inflammation, and evidence suggesting the role of neurogenic inflammation in the pathogenesis of psoriasis. Statins 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.

Astelin (Azelastine) “is indicated for symptomatic treatment of vasomotor rhinitis including rhinorrhea, nasal congestion, and post nasal drip in adults and children 12 years of age and older.

Neurophysiologic factors in fibromyalgia

There has also been a better awareness of the effects of social and psychological factors on fibromyalgia, particularly those related to the reactivity of the stress response on central pain-related neural systems. Researchers have been careful to identify measurable neurophysiologic factors amongst this complex mix of various contributing factors. All of this has taken time. However, current research in fibromyalgia is aligned with cutting-edge research in other chronic pain conditions. There is no satisfactory animal model for fibromyalgia. 

Peripheral neural stimulation

A minority of researchers feel that the sensitivity of the pain-related nervous system in fibromyalgia relates to peripheral neural stimulation priming the sensitization process. This is based on traditional neurophysiologic research, particularly in animals, in which peripheral stimulation initiates the pain response.

I believe more researchers feel that the brain and spinal cord have the main role in modulating peripheral sensory inputs, and when the spinal cord neurons are sensitized by change in brain modulation, various otherwise non-painful stimuli can gain access to the pain-related nervous system and cause fibromyalgia pain. The mechanisms behind these effects have yet to be fully identified.

Related article: Systematic Inflammation found in Fibromyalgia

 

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