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Review

Descending Pain Modulation in Fibromyalgia: A Short Review of Mechanisms and Biomarkers

by
Bruno Daniel Carneiro
1,2,
Sandra Torres
3,
José Tiago Costa-Pereira
1,4,5,
Daniel Humberto Pozza
1,5 and
Isaura Tavares
1,5,*
1
Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
2
Rheumatology Service, Unidade Local de Saúde do Alto Minho, Hospital Conde de Bertiandos, 4990-078 Ponte de Lima, Portugal
3
Unidade de Saúde Familiar São João, Unidade Local de Saúde de Entre Douro e Vouga, 3700-298 São João da Madeira, Portugal
4
Faculty of Nutrition and Food Sciences, University of Porto, 4150-180 Porto, Portugal
5
Institute for Research and Innovation in Health and IBMC (i3S), University of Porto, 4200-135 Porto, Portugal
*
Author to whom correspondence should be addressed.
Diagnostics 2025, 15(21), 2702; https://doi.org/10.3390/diagnostics15212702 (registering DOI)
Submission received: 15 September 2025 / Revised: 17 October 2025 / Accepted: 23 October 2025 / Published: 25 October 2025
(This article belongs to the Special Issue Progress in Chronic Pain: Bridging Basic and Clinical Research)
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Abstract

Fibromyalgia is a prevalent chronic pain disorder characterized by widespread musculoskeletal pain, fatigue, cognitive dysfunction, and sleep disturbances, with high impact in quality of life. Despite extensive research, the pathophysiological mechanisms of fibromyalgia remain partially understood, complicating the diagnosis and treatment. Some evidence underscores the central role of abnormal pain processing, particularly central sensitization and defective descending pain modulation pathways. This review synthesizes and discusses current findings on the neurobiological underpinnings of pain in fibromyalgia, with focus on descending inhibitory control mechanisms and on the role of biomarkers. We integrate data from neurochemical, neuroimaging, and clinical studies to explain how impaired descending modulation contributes to enhanced pain sensitivity and discuss the putative biomarkers associated with changes in descending modulation. A better understanding of descending pain modulation dysfunction in fibromyalgia and related biomarkers is crucial for improving clinical outcomes and developing novel and more effective treatments.

1. Introduction

Fibromyalgia is a complex, multifactorial syndrome affecting approximately 2–4% of the general population worldwide, with a striking female predominance [1,2]. Clinically characterized by chronic widespread musculoskeletal pain, fatigue, sleep disturbances, cognitive dysfunction (“fibro fog”), and mood disorders, fibromyalgia implicates significant challenges for both patients and clinicians due to its heterogeneous presentation and poorly understood etiology [3,4,5,6]. The American College of Rheumatology (ACR) diagnostic criteria, published in 2010 and updated in 2016, emphasize symptom severity and widespread pain but lack objective biomarkers, underscoring the need for deeper mechanistic insights [7].
The burden of fibromyalgia extends beyond physical symptoms, significantly impacting daily functioning, psychosocial well-being, and health care utilization [8,9,10]. Patients experience comorbid conditions such as irritable bowel syndrome, temporomandibular disorders, and migraine, highlighting the systemic nature of fibromyalgia [11]. This complexity demands a comprehensive understanding of the underlying pathophysiology to guide diagnosis, prognosis, and personalized treatment strategies.
Figure 1 summarizes the epidemiology, symptoms, pathophysiology, diagnostic criteria and treatment of fibromyalgia.
Over the past two decades, accumulating evidence has shifted the conceptual framework of fibromyalgia from a purely peripheral nervous system and musculoskeletal disorder, with some studies suggesting that the disease is associated with small fiber neuropathy [12,13,14,15] and others suggesting that fibromyalgia patients exhibited greater variability in muscle fiber size and altered fiber size distribution [16], to a centralized pain syndrome involving aberrant central nervous system (CNS) processing [1,17,18]. In fact, central sensitization (CS), a neuroplastic phenomenon characterized by amplified responsiveness of nociceptive neurons in the spinal cord and brain, is considered a landmark feature driving enhanced pain perception in fibromyalgia [19,20]. Moreover, dysfunction of the descending pain modulatory system (DPMS), which normally balances between inhibitory and facilitatory control, but exerting inhibition in acute pain, has emerged as a critical contributor to persistent pain and symptom amplification in fibromyalgia [21,22,23].
Descending pain modulation involves complex neural circuits spanning cortical, subcortical, and brainstem regions, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), periaqueductal gray (PAG), and rostral ventromedial medulla (RVM) [24]. These pathways utilize endogenous neurotransmitters, namely serotonin (5-HT), noradrenaline (NA), dopamine (D), and opioids, to suppress or facilitate pain signals at the dorsal horn level [25]. Dysfunction in these systems can activate pain facilitation and exacerbate clinical symptoms [26].
Despite advances, the precise mechanisms by which descending pain modulation is impaired in fibromyalgia remain incompletely elucidated. Neuroimaging studies revealed altered brain connectivity and functional changes within DPMS nodes, while neurochemical investigations highlight imbalances in monoaminergic and glutamatergic neurotransmission [27,28,29,30]. Furthermore, a recent multimodal neuroimaging study recruiting 40,000 participants, showed that fibromyalgia was strongly associated with relevant changes in subcortical brain structures involved in descending pain modulatory pathways, namely structural connectivity between PAG and amygdala, as well as between PAG and hypothalamus [31]. Identifying reliable and specific biomarkers associated with this impaired pain inhibition is pivotal for advancing both the pathophysiological understanding and clinical translation.
Given the increasing prevalence of fibromyalgia and its substantial impact on public health, as well as the need for high-quality and objective syntheses of current knowledge, a comprehensive and up-to-date review of the mechanisms underlying pain and dysfunction in descending pain modulation, along with potential biomarkers, is both timely and essential. Such insights will enhance our understanding of diagnostic biomarkers and support the development of novel therapeutic targets tailored to the neurobiological profiles of individual patients.
Therefore, this review aims to provide a synthetic overview of the current scientific evidence on the neurobiological mechanisms of pain in fibromyalgia, with focus on the role of descending pain modulation and the role of biomarkers.

2. Methods

This review includes evidence from the last 3 decades, obtained from the MEDLINE/PubMed and Scopus scientific databases, without any restriction. We included all the articles that summarized evidence about the theme, namely by searching for works using the terms “fibromyalgia”, “pain”, “biomarkers”, “mechanisms” and “descending pain modulation”, after a critical and qualitative analysis of all articles by all the authors. We critically appraise neurophysiological, neurochemical, neuroimaging, and clinical data to delineate how abnormalities in pain inhibitory pathways contribute to symptomatology. Finally, we evaluate the clinical implications and emerging therapeutic strategies targeting these pathways.

3. Pathophysiology of Pain in Fibromyalgia

Fibromyalgia pain is multifactorial and appears to result from complex interactions between peripheral and central nociceptive mechanisms. Although some peripheral tissue abnormalities (e.g., muscle microtrauma or inflammation) may initiate nociceptive input, persistent widespread pain in fibromyalgia predominantly reflects CNS amplification and altered pain processing [32,33,34].
Central sensitization increases excitability and synaptic efficacy of nociceptive neurons in the dorsal horn and higher centers leading to hyperalgesia (exaggerated pain responses to stimuli) and allodynia (pain elicited by normally innocuous stimuli) [35]. Impaired descending pain inhibition leads to dysfunction of brainstem and cortical circuits responsible for endogenous analgesia, resulting in insufficient suppression of nociceptive transmission [36]. Moreover, altered levels and receptor function of key neurotransmitters (e.g., 5-HT and NA) disrupt both pain modulation and affective components of pain [37,38]. Microglia and astrocyte activation in the CNS release pro-inflammatory cytokines and chemokines, which sensitize nociceptive neurons and disrupt neural circuits [39]. Reductions in gray matter volume and altered functional connectivity in pain-processing and modulatory regions further contribute to persistent pain and cognitive symptoms [40,41]. Together, these factors establish a maladaptive pain state in fibromyalgia, characterized by chronic widespread pain, fatigue, and cognitive disturbances.

3.1. Central Sensitization in Fibromyalgia

Central sensitization seems to be a key mechanism underpinning enhanced pain sensitivity in fibromyalgia. It involves increased responsiveness of nociceptive neurons in the spinal dorsal horn and brain to peripheral stimuli [42]. The mechanisms associated with CS are diverse. There are enhanced excitatory synaptic transmission mediated by increased glutamate (Glu) release and N-methyl-D-aspartate (NMDA) receptor activation [43], increased levels of excitatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) [44] and long-term neuroplastic changes, including altered synaptic strength and receptor expression, in pain-related brain regions such as the insula, ACC, thalamus, and PFC [45,46].
Clinical correlates of CS include widespread pain, tenderness, allodynia, and secondary hyperalgesia. Quantitative sensory testing (QST) and functional neuroimaging support the presence of CS in fibromyalgia patients [47,48]. These patients experience an exaggerated increase in perceived pain intensity in response to rapidly repeated noxious stimuli—a phenomenon known as temporal summation of pain [49,50]. However, there are also studies suggesting that fibromyalgia patients are hyperalgesic in spite of a normal modulation of the transmission of nociceptive input [51,52].
The increased pain sensitivity in fibromyalgia is part of complex hypersensitivity to sensory stimuli in general, including visual, auditory, and olfactory inputs. In fact, fibromyalgia patients have exhibited increased brain responses not only to the pain onset but also its offset [53], as well as hypersensitivity to sound and heat [54].

3.2. Dysfunction of Descending Pain Modulation in Fibromyalgia

The DPMS regulates nociceptive transmission through both inhibitory and facilitatory influences originating from cortical and brainstem regions [25]. Its principal components include: (1) the PFC and ACC, which are involved in the cognitive and emotional modulation of pain [55]; (2) the PAG, a midbrain region critical for initiating descending inhibition via endogenous opioids [56]; (3) RVM, which exerts a bidirectional control of nociception by its resident on- and off-cells that facilitate or inhibit spinal nociceptive neurons, respectively [57]; (4) the locus coeruleus (LC), which provides noradrenergic descending projections [58]; and (5) the nucleus raphe magnus (NRM), a key source of serotonergic descending fibers [26].
In healthy individuals, the DPMS may modulates pain signals via neurotransmitters such as 5-HT, NA, D, and endogenous opioids, facilitating adaptive responses to noxious stimuli [59]. Multiple changes in how pain is transmitted and modulated, namely those involving key neurotransmitters, are thought to disrupt the balance between pain-inhibiting and pain-facilitating pathways [59]. This imbalance contributes to the chronification of pain and CS [59].
Numerous studies demonstrate impaired descending inhibition in fibromyalgia. In fact, fibromyalgia patients consistently show reduced descending pain modulation efficiency compared to healthy controls, indicating defective endogenous pain inhibition [50,60,61]. Conditioned pain modulation (CPM), the human correlate of diffuse noxious inhibitory controls (DNIC), reflects DPMS efficacy and is measurable through experimental paradigms [62]. In CPM testing a painful conditioning stimulus is applied in one part of body, which leads to a reduction in pain perception from another, separate painful stimulus applied elsewhere, often on the opposite side. This response illustrates the CNS’s ability to suppress pain signals in one region when another painful input is present, demonstrate an endogenous pain inhibition mechanism [63]. Similarly to other chronic pain conditions, research has indicated that CPM tends to be less effective in fibromyalgia patients [50,64,65,66,67].
Furthermore, functional magnetic resonance imaging (fMRI) studies reveal reduced activity and altered connectivity in DPMS structures, such as diminished PAG and ACC engagement during pain modulation tasks [68,69] and positron emission tomography (PET) imaging shows altered opioid receptor availability in DPMS regions in fibromyalgia [70]. Neurochemical studies reveal decreased serotonergic and noradrenergic tone, impairing descending inhibitory signaling [70,71]. This dysfunction disrupts the balance between pain facilitation and inhibition, promoting persistent pain and symptom exacerbation. Reduced levels of 5-HT and 5-HT-receptor dysfunction decrease descending inhibition and contribute to affective symptoms [72]. Deficits in signaling associated with NA impair pain inhibition and arousal regulation [73]. Altered dopaminergic neurotransmission, involving D, affects reward processing, fatigue, and pain perception [74]. Increased activity of Glu pathways enhances excitatory signaling and CS [33]. Elevated cerebrospinal fluid (CSF) concentrations of SP correlate with pain intensity [75]. The imbalance of these neurotransmitters represents the basis for pharmacologic interventions targeting serotonin-noradrenaline reuptake inhibitors (SNRIs), D agonists, and Glu modulators [76].
An abnormal resting-state functional connectivity of the PAG was found in fibromyalgia patients [77] and these changes result in impaired descending pain inhibition. Patients with fibromyalgia were also found to have altered functional connectivity with the default mode network (a region active when the brain is at rest) and the insula [78]. Altered hub topology within the insula was associated with clinical pain intensity. In line with this, the organization of intrinsic functional brain hubs or communities in patients with fibromyalgia demonstrate decreased neural stability.

Neuroinflammation and Glial Activation

Neuroinflammation involves the activation of the immune cells in the CNS, namely microglia and astrocytes, and subsequent release of pro-inflammatory mediators. This phenomenon plays a significant role in dysregulation of the DPMS [79]. Emerging research implicates neuroinflammatory processes as a critical feature in fibromyalgia pathogenesis (reviewed by Findeisen and collaborators [80]). Activated microglia and astrocytes release cytokines, such interleukins (IL) 6 and 1β and tumor necrosis factor α, and chemokines, that sensitize nociceptive neurons and impair descending modulation [81,82]. Elevated inflammatory markers in CSF and blood have been reported in fibromyalgia [83,84]. Furthermore, recent studies utilizing PET-computed tomography brain imaging with the 18 kDa Translocator Protein (TSPO) binding have revealed a widespread cortical glial activation in fibromyalgia patients [85,86].
Neuroinflammation appears to be a key factor in maintaining CS and is also contribute to comorbid symptoms such as fatigue and cognitive dysfunction [87]. As a result, therapeutic approaches aimed at glial activation and reducing inflammation are currently considered as promising strategies in the management of fibromyalgia [88].

3.3. Brain Structural and Functional Changes

Advanced neuroimaging techniques reveal consistent structural and functional brain abnormalities in fibromyalgia such as: (1) gray matter volume reductions in pain-related regions including the insula, ACC, PFC, and hippocampus [89,90,91]; (2) altered white matter microstructure in pain pathways [92]; and (3) aberrant resting-state functional connectivity within the default mode, salience, and sensorimotor networks [33,93]. A recent study also suggests that individuals with fibromyalgia exhibited changed anticipatory pain processing, marked by reduced activation of the dorsolateral PFC and disrupted connectivity with pain processing brain regions, which may underlie their impaired ability to modulate pain expectations [94].
All these changes correlate with clinical symptom severity and cognitive dysfunction [95] and support the concept of fibromyalgia as a disorder of CNS involving both sensory and affective pain dimensions. Interestingly, multimodal brain imaging demonstrated that gray-matter volumes reduction in patients with fibromyalgia are correlated with the low levels of tissue water content, suggesting neuronal plasticity [96] which is in line with the concept of nociplastic pain.

4. Biomarkers

In fibromyalgia, diagnostic biomarkers may serve as critical tools for delineating pathophysiological mechanisms, stratifying patients into biologically relevant subgroups within this heterogenous pain condition and characterizing molecular and physiological changes associated with the treatment [97,98,99,100].
A widely accepted functional biomarker of descending pain inhibition is the previous referred CPM. In fibromyalgia, the CPM response is significantly diminished, supporting impaired top-down pain modulation and consistent with the concept of CS [62,101,102]. The degree of CPM dysfunction has been found to correlate with clinical symptoms severity and may serve as a predictive marker for treatment response [103].
Advanced neuroimaging techniques including fMRI, PET, and single photon emission computed tomography (SPECT) have demonstrated altered connectivity and increased activity in regions associated with pain perception and modulation [69,104]. In addition, PET imaging using TSPO ligands, such as PBR28 and DPA-714, has revealed increased microglial activation in cortical regions suggesting neuroinflammation as a central mechanism [86,105]. The neuroinflammatory changes were positively correlated with pain intensity and fatigue levels in fibromyalgia, positioning TSPO-PET as a candidate biomarker. Fibromyalgia has also been associated with a low-grade pro-inflammatory profile with elevated levels of IL-6 and IL-8 being repeatedly found in the serum and plasma of fibromyalgia patients, associated with pain intensity, fatigue, and cognitive symptoms [33,106]. Anti-inflammatory cytokines, such as IL-10, may be elevated as a compensatory response [106,107].
Numerous neurochemical alterations associated with DPMS dysfunction have been identified in fibromyalgia with higher potential to be biomarker: (1) elevated serum fluid levels of brain-derived neurotrophic factor (BDNF) have been found in fibromyalgia patients [108]; (2) fibromyalgia patients exhibit higher CSF levels of SP [75]; (3) reduced levels of 5-HT, D, and NA in the CNS and peripheral tissues reflect impaired descending inhibitory neurotransmission [109]; (4) spectroscopy imaging studies employing 1H-MRI (proton nuclear magnetic resonance) have demonstrated higher levels of Glu in pain-processing brain regions of fibromyalgia patients, suggesting Glu as a useful biomarker of pain in in this population [33,110,111].
Epigenetic modifications and non-coding ribonucleic acid (RNA) may regulate genes involved in pain modulation with methylation changes being observed in genes involved in monoaminergic neurotransmission (e.g., solute carrier family 6 member 4—SCL6A4), Glu receptors (e.g., glutamate metabotropic receptor 6—GRM6), and neuroplasticity (e.g., BDNF) [112]. Several microRNA (miR), such as miR-145-5p, miR-23a-3p and miR-21 have been reported to be dysregulated in fibromyalgia and correlated with pain intensity and fatigue. These may serve as non-invasive biomarkers with potential regulatory roles in DPMS [113].
Patients with fibromyalgia often exhibit autonomic imbalance along with dysfunction of the hypothalamic–pituitary–adrenal axis dysfunction, both of which are linked to impaired stress response and pain regulation. Biomarkers in this domain include low cortisol levels [114,115].
Fibromyalgia patients also have higher levels of C-reactive protein, and these higher levels could be associated with higher symptom severity [116,117]. However, a systematic review did not fully support the relation between the levels of C-reactive protein and symptom severity [118].
Table 1 presents a synthetic integration of biomarkers with descending pain modulation in fibromyalgia.

5. Clinical Implications and Therapeutic Perspectives

Understanding descending pain modulation deficits has direct clinical relevance. Regarding pharmacological therapies, SNRIs, such as duloxetine, restore monoaminergic tone and improve pain and mood [119], gabapentinoids modulate excitatory neurotransmission [120] and low-dose naltrexone may reduce neuroinflammation and enhance endogenous opioid activity [121]. Surprisingly, a recent randomized clinical trial suggested that the effects of low-dose naltrexone in fibromyalgia patients may be attributed to a decline in CPM within placebo group than to a robust analgesic effect of the drug [122], underscoring the complexity of fibromyalgia pathophysiology and its treatment.
On the other hand, non-pharmacological therapies, such as cognitive-behavioral therapy (CBT) and mind–body interventions (namely mindfulness-based interventions), and aerobic exercise, improve DPMS function and neuroplasticity [123,124]. Neuromodulation, namely transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) show promise in enhancing descending inhibition [125,126,127].
The role of microbiome in fibromyalgia cannot be overlooked, since recent studies have highlighted its involvement, particularly in modulation of pain during this pathology [128,129,130]. Therefore, these findings suggest that nutritional interventions may offer a promising non-pharmacological therapeutic strategy with the potential to positively fibromyalgia management [131,132].
A better knowledge about biomarkers of DPMS function and neuroinflammation may enable tailored therapies [133].

6. Concluding Remarks

Fibromyalgia represents a complex, multifactorial syndrome characterized by chronic widespread pain, fatigue, cognitive dysfunction, and a host of somatic symptoms. Despite decades of research, its precise etiology remains elusive, with current evidence supporting a CS paradigm involving aberrant pain processing and neuroinflammation. The literature consistently highlights altered CNS function, including dysregulation of neurotransmitters and changes in brain connectivity patterns that correlate with symptom severity [1,33,69]. These neurobiological alterations offer a plausible mechanistic explanation for the hallmark symptoms of fibromyalgia and underscore the syndrome’s classification as a disorder of central pain amplification rather than purely peripheral pathology.
In Figure 2, we summarized the pain pathways and neurotransmitters in fibromyalgia.
However, the heterogeneity of clinical presentations and overlap with other central sensitivity syndromes complicates diagnosis and management. Under- and misdiagnosis remain challenges, often leading to delayed treatment and reduced quality of life [4]. This calls for continued refinement of diagnostic criteria and the development of objective biomarkers, which remain an unmet need despite promising findings in neuroimaging and CSF inflammatory markers [21,95].
Therapeutic approaches have evolved to target the underlying neurochemical imbalances and CS processes. Pharmacologic interventions such as duloxetine and pregabalin, which modulate 5-HT and NA pathways, provide symptomatic relief for some patients, but efficacy is highly variable [119,120]. Interestingly in a recent study, carried out in rats, was outline the antidepressant aptitude of milnacipran and vanillin through activating Wnt/β-catenin signaling in the hippocampus in reserpine-induced fibromyalgia [134]. Non-pharmacological strategies, including CBT and graded exercise, address the biopsychosocial aspects and demonstrate substantial benefit, emphasizing the importance of multidisciplinary care [123,124]. In fact, international recommendations for the treatment of fibromyalgia highlight the non-pharmacological approaches as the first line therapy, establishing three essential components: patient education; CBT; and exercise [1,135,136,137,138].
Other emerging therapies such as low-dose naltrexone, neuromodulation techniques and dietary intervention are promising but require further rigorous trials [88,125,129].
Future research should focus on unraveling the interplay between genetic predisposition, neuroimmune interactions, and environmental triggers to better stratify patients and personalize treatment. Advances in neuroimaging and molecular biomarkers may allow clinicians to move beyond symptom-based diagnosis toward precision medicine. Additionally, understanding the role of neuroinflammation and glial activation could open novel therapeutic avenues targeting immune-neural crosstalk in chronic pain syndromes. The presence of multiple biomarker domains in fibromyalgia reflecting impaired descending pain modulation provide a robust framework to objectively assess the status of the DPMS. These biomarkers hold promise not only for improving diagnostic accuracy but also for patient stratification, prognosis, and response prediction to mechanism-based treatments in fibromyalgia.
In this review, we highlighted that fibromyalgia is best conceptualized as a disorder of CNS dysregulation with significant biopsychosocial dimensions. While progress has been made in elucidating its pathophysiology and improving management, comprehensive, individualized treatment plans remain essential to address the syndrome’s complexity and improve patient outcomes, and for this it is urgent and essential to understand the role of descending modulation of pain in fibromyalgia and the role of the associated biomarkers.
In conclusion, fibromyalgia is a prototypical centralized pain syndrome driven by complex neurobiological mechanisms. CS and impaired descending pain modulation underlie the amplified pain experience. This dysregulation is further sustained by neurotransmitter imbalances, neuroinflammation, and brain structural and functional alterations. Advances in neurobiology and neuroimaging hold promise for increasing our understanding of fibromyalgia and offer new avenues for precision medicine approaches. Future research should focus on identifying more rigorous biomarkers, clarifying their role, and the development of targeted therapies that restore endogenous pain inhibitory mechanisms to alleviate the burden of fibromyalgia.

Author Contributions

Conceptualization, B.D.C., D.H.P. and I.T.; investigation, B.D.C., S.T. and J.T.C.-P.; imaging, B.D.C.; writing—original draft preparation, B.D.C., S.T. and J.T.C.-P.; writing—review and editing, B.D.C., S.T., J.T.C.-P., D.H.P. and I.T.; project administration, B.D.C., J.T.C.-P., D.H.P. and I.T. All authors have read and agreed to the published version of the manuscript.

Funding

This study was performed within the scope of the grant “Cátedra de Medicina da Dor” from Fundação Grunenthal.

Data Availability Statement

All data generated during this study are available upon reasonable request from the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ACCanterior cingulate cortex
ACRAmerican College of Rheumatology
BDNFbrain-derived neurotrophic factor
CBTcognitive-behavioral therapy
CGRPcalcitonin gene-related peptide
CNScentral nervous system
CPMconditioned pain modulation
CScentral sensitization
CSFcerebrospinal fluid
Ddopamine
DNICdiffuse noxious inhibitory controls
DPMSdescending pain modulatory system
FMfibromyalgia
fMRIfunctional magnetic resonance imaging
Gluglutamate
GRM6glutamate metabotropic receptor 6
1H-MRIproton nuclear magnetic resonance
HPAhypothalamic–pituitary–adrenal axis
HRVheart rate variability
5-HTserotonin
ILinterleukin
LClocus coeruleus
miRmicro ribonucleic acid
NAnoradrenaline
NMDAN-methyl-d-aspartate
NRMnucleus raphe magnus
PAGperiaqueductal gray
PETpositron emission tomography
PFCprefrontal cortex
QSTquantitative sensory testing
RNAribonucleic acid
RVMrostral ventromedial medulla
SCL6A4solute carrier family 6 member
SPsubstance P
SNRIsserotonin-norepinephrine reuptake inhibitors
SPECTsingle photon emission computed tomography
tDCStranscranial direct current stimulation
TMStranscranial magnetic stimulation
TSPO18 kDa Translocator Protein

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Figure 1. Infogram about fibromyalgia. AAPT, ACTTION (Addiction Clinical Trial Translations Innovations Opportunities and Networks)-APS (American Pain Society) Pain Taxonomy; ACR, American College of Rheumatology; F, female; FM, fibromyalgia; M, male; SSS, symptom severity score; WPI, widespread pain index. Parts of the figure were drawn using pictures from Servier Medical Art by Servier that is licensed under Attribution 4.0 International.
Figure 1. Infogram about fibromyalgia. AAPT, ACTTION (Addiction Clinical Trial Translations Innovations Opportunities and Networks)-APS (American Pain Society) Pain Taxonomy; ACR, American College of Rheumatology; F, female; FM, fibromyalgia; M, male; SSS, symptom severity score; WPI, widespread pain index. Parts of the figure were drawn using pictures from Servier Medical Art by Servier that is licensed under Attribution 4.0 International.
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Figure 2. Infogram about pain pathways and neurotransmitters in fibromyalgia. ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; D, dopamine; DH, dorsal horn; DRG, dorsal root ganglion; EnOp, endogenous opioids; FM, fibromyalgia; Glu, glutamate; 5-HT, serotonin; NA, noradrenaline; PAG, periaqueductal gray; PFC, prefrontal cortex; RVM, rostral ventromedial medulla; SP, substance P; Tha, thalamus. Parts of the figure were drawn using pictures from Servier Medical Art by Servier that is licensed under Attribution 4.0 International.
Figure 2. Infogram about pain pathways and neurotransmitters in fibromyalgia. ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; D, dopamine; DH, dorsal horn; DRG, dorsal root ganglion; EnOp, endogenous opioids; FM, fibromyalgia; Glu, glutamate; 5-HT, serotonin; NA, noradrenaline; PAG, periaqueductal gray; PFC, prefrontal cortex; RVM, rostral ventromedial medulla; SP, substance P; Tha, thalamus. Parts of the figure were drawn using pictures from Servier Medical Art by Servier that is licensed under Attribution 4.0 International.
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Table 1. Integration of biomarkers with descending pain modulation in fibromyalgia.
Table 1. Integration of biomarkers with descending pain modulation in fibromyalgia.
CategoryExample BiomarkersRelation with Descending Pain Modulation
FunctionalCPMAllow direct measure of endogenous inhibitory system
NeuroimagingTSPO-PET; fMRIIndicators of neuroinflammation and cortical dysregulation
NeurochemicalBDNF; SP; 5-HTIndicators of excitatory and inhibitory neurotransmission
ImmunologicalIL-6; IL-8; IL-10Indicators of neuroimmune involvement and sensitization
EpigeneticGRM6; BDNF; miRIndicators of genetic regulation of DPMS
Hypothalamic–pituitary–adrenal axis controlCortisolIndicators of systemic dysregulation affecting pain
Legend: BDNF, brain-derived neurotrophic factor; CPM, conditioned pain modulation; DPMS, descending pain modulatory system; fMRI, functional magnetic resonance imaging; GRM6, glutamate metabotropic receptor 6; 5-HT, serotonin; IL, interleukin; miR, micro ribonucleic acid; SP, substance P; TSPO-PET, 18 kDa Translocator Protein-positron emission tomography.
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MDPI and ACS Style

Carneiro, B.D.; Torres, S.; Costa-Pereira, J.T.; Pozza, D.H.; Tavares, I. Descending Pain Modulation in Fibromyalgia: A Short Review of Mechanisms and Biomarkers. Diagnostics 2025, 15, 2702. https://doi.org/10.3390/diagnostics15212702

AMA Style

Carneiro BD, Torres S, Costa-Pereira JT, Pozza DH, Tavares I. Descending Pain Modulation in Fibromyalgia: A Short Review of Mechanisms and Biomarkers. Diagnostics. 2025; 15(21):2702. https://doi.org/10.3390/diagnostics15212702

Chicago/Turabian Style

Carneiro, Bruno Daniel, Sandra Torres, José Tiago Costa-Pereira, Daniel Humberto Pozza, and Isaura Tavares. 2025. "Descending Pain Modulation in Fibromyalgia: A Short Review of Mechanisms and Biomarkers" Diagnostics 15, no. 21: 2702. https://doi.org/10.3390/diagnostics15212702

APA Style

Carneiro, B. D., Torres, S., Costa-Pereira, J. T., Pozza, D. H., & Tavares, I. (2025). Descending Pain Modulation in Fibromyalgia: A Short Review of Mechanisms and Biomarkers. Diagnostics, 15(21), 2702. https://doi.org/10.3390/diagnostics15212702

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