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Cited by 227Pain Mechanisms and TreatmentsFibromyalgia and Chronic Fatigue Syndrome ResearchPain Management and Treatment

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Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions

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Eller-Smith, Olivia C., Nicol, Andrea L., Christianson, Julie A.·2018·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2018.00035PMC PMC5816755
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Abstract

Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, migraine, and temporomandibular disorder. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life. The high degree of symptom comorbidity and a lack of definitive underlying etiology make these syndromes notoriously difficult to treat. The main purpose of this review article is to discuss potential mechanisms of centrally-driven pain amplification and how they may contribute to increased comorbidity, poorer pain outcomes, and decreased quality of life in patients diagnosed with centralized pain syndromes, as well as discuss emerging non-pharmacological therapies that improve symptomology associated with these syndromes. Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis is commonly associated with centralized pain disorders. The HPA axis is the primary stress response system and its activation results in downstream production of cortisol and a dampening of the immune response. Patients with centralized pain syndromes often present with hyper- or hypocortisolism and evidence of altered downstream signaling from the HPA axis including increased Mast cell (MC) infiltration and activation, which can lead to sensitization of nearby nociceptive afferents. Increased peripheral input via nociceptor activation can lead to "hyperalgesic priming" and/or "wind-up" and eventually to central sensitization through long term potentiation in the central nervous system. Other evidence of central modifications has been observed through brain imaging studies of functional connectivity and magnetic resonance spectroscopy and are shown to contribute to the widespreadness of pain and poor mood in patients with fibromyalgia and chronic urological pain. Non-pharmacological therapeutics, including exercise and cognitive behavioral therapy (CBT), have shown great promise in treating symptoms of centralized pain.

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Crossref · 10.3389/fncel.2018.00035

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Figure 1 Under normal conditions, an acute stressor will signal the paraventricular nucleus (PVN) of the hypothalamus to release corticotropin-releasing factor (CRF) into the hypophyseal portal veins, which causes the anterior pituitary gland to release adrenocorticotrophic hormone (ACTH). Circulating ACTH signals the adrenal cortex to release glucocorticoids (GC) that have downstream metabolic effects. A negative feedback loop is established to turn off activation of the hypothalamic-pituitary-adrenal (HPA) axis by suppressing the production of CRF and ACTH upon cessation of the initial stressor. The hippocampus and the amygdala play inhibitory and excitatory roles in regulation of the HPA axis, respectively. CRF released upon HPA axis activation also has peripheral effects. Mast cells (MC) can become activated by CRF, causing the release of cytokines and growth factors that have reciprocal interactions with peripheral nociceptors. Nociceptor activation signals through the dorsal horn of the spinal cord, leading to activation of supraspinal somatosensory brain regions. The descending pain pathway also plays a role in the regulation of painful experiences.
Figure 1 Under normal conditions, an acute stressor will signal the paraventricular nucleus (PVN) of the hypothalamus to release corticotropin-releasing factor (CRF) into the hypophyseal portal veins, which causes the anterior pituitary gland to release adrenocorticotrophic hormone (ACTH). Circulating ACTH signals the adrenal cortex to release glucocorticoids (GC) that have downstream metabolic effects. A negative feedback loop is established to turn off activation of the hypothalamic-pituitary-adrenal (HPA) axis by suppressing the production of CRF and ACTH upon cessation of the initial stressor. The hippocampus and the amygdala play inhibitory and excitatory roles in regulation of the HPA axis, respectively. CRF released upon HPA axis activation also has peripheral effects. Mast cells (MC) can become activated by CRF, causing the release of cytokines and growth factors that have reciprocal interactions with peripheral nociceptors. Nociceptor activation signals through the dorsal horn of the spinal cord, leading to activation of supraspinal somatosensory brain regions. The descending pain pathway also plays a role in the regulation of painful experiences.CC BY · PubMed Central
Figure 2 Chronic early life or adult stress leads to alteration in limbic regulation of the HPA axis. This is due to increased CRF expression and drive from the amygdala (1) and decreased glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) expression in hippocampus, which dampens inhibition (2). These changes ultimately lead to increased CRF release from the hypothalamus (3), increased and prolonged release of ACTH after cessation of the stressor (4), and increased glucocorticoid (GC) production (5) with decreased negative feedback at higher structures. Increased CRF release leads to greater MC activation and infiltration (6) leading to enhanced peripheral nociceptor interaction (7). Increased peripheral drive can lead to hyperalgesic priming (8) and/or wind-up (9), eventually increasing ascending pain signaling, while simultaneously decreasing descending inhibition (10).
Figure 2 Chronic early life or adult stress leads to alteration in limbic regulation of the HPA axis. This is due to increased CRF expression and drive from the amygdala (1) and decreased glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) expression in hippocampus, which dampens inhibition (2). These changes ultimately lead to increased CRF release from the hypothalamus (3), increased and prolonged release of ACTH after cessation of the stressor (4), and increased glucocorticoid (GC) production (5) with decreased negative feedback at higher structures. Increased CRF release leads to greater MC activation and infiltration (6) leading to enhanced peripheral nociceptor interaction (7). Increased peripheral drive can lead to hyperalgesic priming (8) and/or wind-up (9), eventually increasing ascending pain signaling, while simultaneously decreasing descending inhibition (10).CC BY · PubMed Central
Figure 3 Non-pharmaceutical interventions restore proper signaling within the HPA axis and between higher structures. Exercise increases dendritic complexity and BDNF expression in the hippocampus, which restores negative input onto the hypothalamus to restore proper HPA axis output (1). Decreased CRF release stabilizes MC activation and infiltration associated with chronic pain disorders (2), thereby reducing peripheral nociceptive input. Exercise influences the descending pain pathway, likely through release of endogenous opioids, increasing neuronal activity, and balancing excitatory and inhibitory transmission (3). Cognitive behavioral therapy (CBT) alters the intrinsic functional connectivity (iFC) between brain regions associated with pain management, including connections between the prefontal cortex (PFC) and amygdala and somatosensory cortex and the basal ganglia network (BGN) (4). Cortical and hippocampal gray matter densities are also increased in patients following CBT (5).
Figure 3 Non-pharmaceutical interventions restore proper signaling within the HPA axis and between higher structures. Exercise increases dendritic complexity and BDNF expression in the hippocampus, which restores negative input onto the hypothalamus to restore proper HPA axis output (1). Decreased CRF release stabilizes MC activation and infiltration associated with chronic pain disorders (2), thereby reducing peripheral nociceptive input. Exercise influences the descending pain pathway, likely through release of endogenous opioids, increasing neuronal activity, and balancing excitatory and inhibitory transmission (3). Cognitive behavioral therapy (CBT) alters the intrinsic functional connectivity (iFC) between brain regions associated with pain management, including connections between the prefontal cortex (PFC) and amygdala and somatosensory cortex and the basal ganglia network (BGN) (4). Cortical and hippocampal gray matter densities are also increased in patients following CBT (5).CC BY · PubMed Central

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Metadata

Authors
Eller-Smith, O. C., Nicol, A. L., & Christianson, J. A.
Affiliations
University of Kansas Medical Center (US)
Corresponding author
Christianson, Julie A.
ORCID
Christianson, Julie A.
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2018-02-13
Volume
12
Pages
35-35
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2018.00035
PMC
PMC5816755
OpenAlex
W2793570991
Cited by
227
References
235
Citations by year
2026: 31 · 2025: 24 · 2024: 20 · 2023: 31 · 2022: 31 · 2021: 31 · 2020: 26 · 2019: 23 · 2018: 10
FWCI
2.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (DK099611, DK103872, GM123320, HD057850)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
fibromyalgia, chronic pelvic pain, migraine, temporomandibular disorders, central sensitization, HPA axis dysregulation, mast cells, hyperalgesic priming, wind-up, long-term potentiation, functional connectivity, non-pharmacological treatment, physical activity, cognitive behavioral therapy, comorbidities, quality of life

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