Neurogenic inflammation in Musculoskeletal Condition

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Introduction[edit | edit source]

Neurogenic inflammation is the physiological process by which mediators are released directly from the cutaneous nerves to initiate an inflammatory reaction. This results in production of local inflammatory responses including erythema, swelling, temperature increase, tenderness, and pain[1][2][3][4][5].

Fine unmyelinated afferent somatic C-fibers, which respond to low intensity mechanical and chemical stimulations, are largely responsible for the release of inflammatory mediators. When stimulated, these nerve fibers in the cutaneous nerves release active neuropeptides – substance P and calcitonin gene related peptide (CGRP) – rapidly into the microenvironment, triggering a series of inflammatory responses[1][2][3][4][5][6].

Although neurogenic inflammation and immunologic inflammation can exist at the same time, the two are not clinically identical[1]. There is an important distinction from immunogenic inflammation, which is the very first protective and reparative response generated by the immune system when a pathogens enters a body[2][7] while neurogenic inflammation involves a direct relationship betwen the nervous system and the inflamatory reactions.[1] Although neurogenic inflammation and immunologic inflammation can exist concurrently, the two are not clinically identical.

Mechanism[edit | edit source]

In order to fully appreciate the involvement of neurogenic inflammation in various clinical conditions, it is important to understand its mechanisms of action. To date, two possible mechanisms of neurogenic inflammation – backfiring[1] and neurogenic switching[8][9] – have been proposed.

Under normal circumstances, peripheral tissue damage in the body will cause sensory neurones to send an impulse via the dorsal root ganglion into the central nervous system (CNS) for further processing. In some cases, however, instead of the impulse being transmitted centrally, it may shoot down the axon directly, causing neuropeptide release at the distal end of the neurone. This phenomenon is known as backfiring and was introduced as a mechanism for neurogenic inflammation by Butler and Moseley(2003)[1]. Consequently, the release of neuropeptides by the irritated neurone induces inflammation in the distal tissues. Sustained inflammation was also suggested to be caused by persistent backfiring[1].

Another proposed mechanism is known as neurogenic switching. Under this mechanism, the sensory impulse generated locally gets normally transmitted from the site of activation to the CNS, which then creates an efferent signal to regulate the inflammation. However, the signal is rerouted via the CNS to a distant location and produces neurogenic inflammation at the second location. In fact, neurogenic switching was further illustrated using the multiple chemical sensitivity syndromes, in which detection of chemical irritants by the respiratory system triggers inflammatory responses in various secondary organ systems. Similarly, this neuronal pathway can be a possible explanation[8][9].

Clinical Examples[edit | edit source]

Clinically, involvement of neurogenic inflammation has been recognized in a number of inflammatory disorders. Neurogenic inflammation has also been implicated in the pathophysiology of numerous diseases, including complex regional pain syndrome, migraine, and irritable bowel and bladder syndromes. However,in the setting of wound healing, neurogenic inflammation helps maintain tissue integrity and facilitate tissue repair.[10]

Complex regional pain syndrome[edit | edit source]

Complex Regional Pain Syndrome (CRPS) is a multi-system chronic pain disorder. It is characterized by pain and inflammation with abnormalities in the sensory, trophic, autonomic, and motor systems[11]. Commonly reported in patients after a stroke, surgery, or bone fracture, CRPS is a complication that can possibly cause damage to the peripheral nerves. In fact, sympathetic innervation becomes evident after the nerve injury caused by CRPS[11][1][2].

CRPS can be further classified into Type I and Type II, with Type I being reported in the majority of patients experiencing CRPS. In Type I CRPS, also known as reflex sympathetic dystrophy, nerve lesions are usually not observable. On the other hand, evidence of nerve damage is generally present in Type II CRPS, making the condition more painful and harder to control[1].

Clinically, CRPS patients are presented with severe pain, inflammatory symptoms, allodynia, thermal and mechanical hyperalgesia, changes in sweating, abnormal nail and hair growth, and muscle weakness. Patients may also experience paresthesia or sensation loss in affected sites[11][3][4][5].

In CRPS, sympathetic pain is caused by the tonic activity of nociceptor afferents following a nerve injury. Peripheral nociceptors are sensitized as a result, leading to hyperalgesia[3][4][5]. As these peripheral nociceptors are readily stimulated, NI is likely to take place in patients with CRPS. To investigate this relationship, studies have been conducted to observe the neuropeptide release following transcutaneous electrical C-fiber stimulation. It was found that a remarkable amount of CGRP and substance P extravasation occurred[6][7]. Furthermore, it was suggested that the NI could either be due to the direct release of inflammatory neuropeptides from the primary afferents, or an impaired neuropeptide inactivation in the peripheral tissues[8][9]. A doppler scanning study reflected that axon reflex vasodilatation increased significantly in the affected limb of CRPS patients, further supporting a strong correlation between cutaneous nerve damage in CRPS and the inflammatory mediators release[7].

Neurogenic Inflammation in Fibromyalgia[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Butler DS, Moseley GL 2003 Explain pain, Noigroup Publications.
  2. 2.0 2.1 2.2 2.3 Chiu IM, von Hehn CA, Woolf CJ 2012 Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nature neuroscience 15: 1063-7.
  3. 3.0 3.1 3.2 3.3 Richardson JD, Vasko MR 2002 Cellular mechanisms of neurogenic inflammation. The Journal of pharmacology and experimental therapeutics 302: 839-45.
  4. 4.0 4.1 4.2 4.3 Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T 2003 Modern aspects of cutaneous neurogenic inflammation. Archives of Dermatology 139: 1479-88.
  5. 5.0 5.1 5.2 5.3 Zegarska B, Lelinska A, Tyrakowski T 2006 Clinical and experimental aspects of cutaneous neurogenic inflammation. Pharmacological reports : PR 58: 13-21.
  6. 6.0 6.1 Skaper SD, Facci L, Giusti P 2014 Mast cells, glia and neuroinflammation: partners in crime? Immunology 141: 314-27.
  7. 7.0 7.1 7.2 Rhoades R and Bell D 2012 Medical physiology : principles for clinical medicine, Philadelphia.
  8. 8.0 8.1 8.2 Meggs WJ 1995 Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity. Environmental health perspectives 103: 54-6
  9. 9.0 9.1 9.2 Meggs WJ 1993 Neurogenic inflammation and sensitivity to environmental chemicals. Environmental health perspectives 101: 234-8.
  10. 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.
  11. 11.0 11.1 11.2 Freedman M, Greis AC, Marino L, Sinha AN, Henstenburg J 2014 Complex regional pain syndrome: diagnosis and treatment. Physical Medicine and Rehabilitation Clinics of North America 25: 291-303