Dysfunctional Neurotransmitter Systems in Fibromyalgia, Their Role in Central Stress Circuitry and Pharmacological Actions on These Systems

Abstract

Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis) have been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms. Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the body's stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia. As we outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis.

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“…Moreover, a deficient serotonin system is strongly associated with major depression. Increased levels of intracerebral substance P have been associated with increased anxiety-like behaviour in animals [15]. Another observation points out that the nervous system role in FMS etiopathogenesys is the higher sympathetic activity found in these patients, thus reflecting a higher night heart rate variability, correlating this alteration to several symptoms including pain severity [16].…”

“…For example, central serotonin and noradrenalin are important in endogenous pain inhibitory pathways; substance P is a neuropeptide that is important for spinal nociception and glutamate plays an important role in nociception, as it has excitatory and sensitizing effects. In FMS patients, serotonin, dopamine and noradrenalin levels appear to be decreased, possibly contributing to dysfunctional descending pathways and resulting in attenuated descending inhibition [15]. Cerebrospinal fluid concentrations of substance P and glutamate have been found to increase.…”

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“…Other excitatory neurotransmitters and pro-nociceptive compounds, such as substance P, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) are all elevated in CSF of FMS patients [301,308,309]. In contrast, significantly lower levels of the major inhibitory neurotransmitter of the central nervous system, γ-aminobutyric acid (GABA), were detected in the right anterior insula of FMS patients compared to healthy controls [310].…”

“…Substance P, glutamate, NGF and BDNF are among the factors capable of activating glial cells and inducing the production of pro-inflammatory cytokines and chemokines like IL-8 [396]. Elevated concentrations of these activating substances have been detected in the CSF of FMS patients compared to normal controls or normative values [301,308,309].…”

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“…FM patients have abnormal responses to stress and an inadequate reaction to stressful events which appear related to functional alterations of the ANS (dysautonomia) and neuroendocrine abnormalities of the hypothalamic-pituitaryadrenal (HPA) axis [24]. The HPA axis in FM shows a decreased cortisol response, and increased adrenocorticosteriod hormone (ACTH) activity to a corticotrophinreleasing factor challenge [17].…”