Neurobiology of fibromyalgia and chronic widespread pain

Abstract

Fibromyalgia is the current term for chronic widespread musculoskeletal pain for which no alternative cause can be identified. The underlying mechanisms, in both human and animal studies, for the continued pain in individuals with fibromyalgia will be explored in this review. There is a substantial amount of support for alterations of central nervous system nociceptive processing in people with fibromyalgia, and that psychological factors such as stress can enhance the pain experience. Emerging evidence has begun exploring other potential mechanisms including a peripheral nervous system component to the generation of pain and the role of systemic inflammation. We will explore the data and neurobiology related to the role of the CNS in nociceptive processing, followed by a short review of studies examining potential peripheral nervous system changes and cytokine involvement. We will not only explore the data from human subjects with fibromyalgia but will relate this to findings from animal models of fibromyalgia. We conclude that fibromyalgia and related disorders are heterogenous conditions with a complicated pathobiology with patients falling along a continuum with one end a purely peripherally driven painful condition and the other end of the continuum is when pain is purely centrally driven.

Keywords: central sensitization; chronic pain; fibromyalgia; hyperalgesia; neurobiology; pain.

Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1

This is the first fMRI study in fibromyalgia. Individuals with fibromyalgia (in red triangle) were given a low intensity stimulus (shown in top left panel) and this led to moderate pain (a 0–20 Gracely scale was used to rate pain intensity). Their fMRI BOLD responses were compared to controls given approximately the same intensity stimulus (blue box) or a higher intensity stimulus that was necessary to cause the same amount of pain (green circle). There was no significant neuronal activation from this low intensity stimulus in the controls, but there was in fibromyalgia patients, and these areas of neuronal activation overlapped significantly with the brain activation pattern of the controls given nearly twice as much pressure, which was what was needed to cause comparable amounts of pain.

Figure 2

Central mechanisms involved in the non-inflammatory muscle pain model induced by repeated injections of pH 4.0 saline into the gastrocnemius muscle. A. The rostral ventromedial medulla (RVM) was examined since it sends projections to the spinal cord to facilitate nociception. B. Glutamate release in response to the first and second injection of acidic saline was examined by microdialysis of the RVM. The graph shows an increase in glutamate in response to the second injection of pH 4.0, but not the first. HPLC trace shows amino acids measured in a sample microdialysis sample. Reproduced from (Radhakrishnan and Sluka, 2009). C. Local anesthetic microinjected into the RVM prior to the second injection (arrow) prevents the development of muscle hyperalgesia to repeated acid injection 24 hours later. Reproduced from (Tillu et al., 2008). D. Microinjection of the NMDA receptor antagonist of AP5, dose dependently reverses the mechanical hyperalgesia of the paw induced by repeated acid injection. Reproduced from (da Silva et al., 2010a). E. Repeated injections of acidic saline increase the phosphorylation of the NDMA receptor, NR1 subunit (p-NR1). Images show the staining for pNR1 in the RVM in animals injected with pH 7.2 and those injected with pH 4.0. The graph shows a significant increase in the number of positively labeled p-NR1 cells in the RVM. Reproduced from (Sluka et al., 2013). F, G. Downregulation of the NR1 subunit, using an FIV vector expressing an miRNA to NR1, prevents the development of paw (F) and muscle (G) hyperalgesia induced by repeated acid injection. Reproduced from (da Silva et al., 2010b).

Figure 3

The fatigue-induced model and the role of local manipulation of ASICs and macrophages. A. The model is induced by repeated injections of pH 5.0 saline in combination with electrically induced fatigue of the gastrocnemius muscle. Muscle hyperalgesia is assessed by examining the withdrawal threshold to force applied by a pair of tweezers. B. Example of the force output of the muscle during the 6 minute fatiguing task. There is approximately a 50% decrease in force representing muscle fatigue. C. Muscle withdrawal thresholds after pH 5.0 injections with the fatigue stimulus show a significant decrease (red) when compared to thresholds before, or to thresholds from those that received pH 5.0 alone (green) or fatigue alone (blue). D. There is no decrease in withdrawal thresholds in the fatigue-induced hyperalgesia model in ASIC3 knockout mice (red) when compared to ASIC1 knockout mice (blue) or wild-type controls (green). E. Blockade of ASIC3 results in a dose-dependent blockade of the hyperalgesia induced in the fatigue-induced pain model. F. The fatigue stimulation increases the number of macrophages in muscle when compared to naïve animals that do not receive the fatigue stimulation. G. Removal of macrophages with clodronate liposomes locally in the muscle prevents the hyperalgesia in the fatigue-induced pain model (red) when compared to control liposomes (blue). Reproduced from (Gregory et al., 2013, Gregory et al., 2015b).