Low-dose naltrexone (LDN) is gaining popularity as a pharmacological treatment option since it was shown in 2009 to reduce symptom severity in several conditions, including fibromyalgia, Crohn’s disease, multiple sclerosis (MS), and complex regional pain syndrome (CRPS).  Low dosages may operate as an anti-inflammatory agent in the central nervous system, via action on microglial cells, which appears to be independent from naltrexone’s recognized activity on opioid receptors at higher dosages.

Brain inflammation is a key factor of MS, Alzheimer’s, Parkinson’s, ALS, and most other major neurodegenerative diseases. Naltrexone is a medication that blocks the effects of drugs known as opiates, or narcotics (a class that includes morphine, heroin, or codeine) and is known to stop activated microglia from producing inflammatory chemicals.  Low-dose naltrexone (LDN) is thought to produce anti-inflammatory effects mainly by antagonizing the activity of glial cells (Mattioli et al., 2010), which suggests that glial modulators may be beneficial for fibromyalgia and perhaps other subgroups of chronic pain patients (Loggia et al., 2015).

Although fibromyalgia is often considered an arthritis-related condition, it is not truly a form of arthritis (a disease of the joints) because it does not cause inflammation or damage to the joints, muscles, or other tissues.  “Fibromyalgia is about neuroinflammation in the central nervous system [CNS]," said Dr. Jarred Younger, associate professor of psychology and director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham. “The key to treatment is to reduce that inflammatory process in the brain. We have to discover and employ both pharmaceutical treatments and other interventions that can get to the CNS and target the cells that drive the inflammation.”  

Research on neurogenic neuroinflammation, found to occur in both fibromyalgia and CRPS, may be valuable in understanding new therapeutical targets.  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.

FM does not respond to common anti-inflammatories and does not seem to be an inflammatory disorder in the classic sense, but inflammatory processes may still be involved. Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells.  Known as astrocytes and microglia, these resident brain cells can perform immune functions in the nervous system. There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating nociceptive sensory neurons. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization.

Cytokines can be functionally divided into two groups:  those that are proinflammatory and those that are essentially anti-inflammatory but that promote allergic responses.   In 2013 researchers at Virginia Commonwealth University found marked reduction in TH2 cytokines such as Il-4, IL-5, and IL-13, which supports the role of inflammation and provides strong evidence of immune dysregulation in FM. 

Normally, glial activation is an adaptive defensive mechanism that can contribute to handling acute stress, limiting tissue damage, and restoring homeostasis. However, when malfunctioning (and, in particular when it does not get resolved during the post-acute or early chronic stage after an injury event) (Rolls et al., 2009) glial activation can have deleterious effects, and turn into the primary pathogenic element (Pekny and Pekna, 2014). Several animal studies have now established that glial activation is a key contributing factor in persistent pain.

The term “gliopathy” is proposed to describe the dysfunctional and maladaptive response of glial cells, specifically astrocytes and microglia, to neural injury that is initiated by the sudden injury induced increase in extracellular concentrations of glutamate and concomitant production of several proinflammatory molecules.

Recently, key molecules driving brain inflammation were identified by UNC researcher Dr. Jenny Ting,   “Our study shows how two proteins that control inflammation are crucial to a particular kind of brain inflammation.” These molecules are present at abnormally high levels in the brains of people with multiple sclerosis. Underscoring the likely clinical relevance of these findings, the group found high levels of [intracellular protein] NLRC4 in astrocytes and microglia from the brain-inflamed mice, as well as in biopsied brain tissue from multiple sclerosis patients. 

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