Neurogenic inflammation in Musculoskeletal Condition
Neurogenic inflammation (NI) 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 painCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
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 responsesCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
Although neurogenic inflammation and immunologic inflammation can exist at the same time, the two are not clinically identicalCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. There is an important distinction from immunogenic inflammation, which is the very first protective and reparative response generated by the immune system when a pathogen enters the bodyCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title while neurogenic inflammation involves a direct relationship between the nervous system and the inflammatory reactionsCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. Although neurogenic inflammation and immunologic inflammation can exist concurrently, two are not clinically identical.
Mechanism
In order to fully appreciate the involvement of NI in various clinical conditions, it is important to understand its mechanisms of action. To date, two possible mechanisms of NI – backfiringCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title and neurogenic switchingCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title – 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 NI by Butler and Moseley(2003)Cite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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 backfiringCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
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 NI 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 explanationCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
Clinical Examples
Clinically, involvement of NI has been recognized in a number of inflammatory disorders.
Complex regional pain syndrome
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 systemsCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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 CRPSCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
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 controlCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
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 sitesCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title.
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 hyperalgesiaCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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 occurredCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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 tissuesCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive titleCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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 release20.
