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An imbalance between excitatory and inhibitory neurotransmission has been linked to fibromyalgia (FM). Magnetic resonance spectroscopy has shown increased levels of glutamate in the insula and posterior cingulate cortex in FM as well as reduced insular levels of gamma-aminobutyric acid (GABA). Both of these changes have been associated with increased pain sensitivity. However, it is not clear whether excitatory and/or inhibitory neurotransmission is altered across the brain. Therefore, the aim of this study was to quantify GABAA receptor concentration on the whole brain level in FM to investigate a potential dysregulation of the GABAergic system. Fifty-one postmenopausal women (26 FM, 25 matched controls) underwent assessments of pain sensitivity, attention and memory, psychological status and function, as well as positron emission tomography imaging using a tracer for GABAA receptors, [F]flumazenil. Patients showed increased pain sensitivity, impaired immediate memory, and increased cortical GABAA receptor concentration in the attention and default-mode networks. No decrease of GABAA receptor concentration was observed. Across the 2 groups, GABAA receptor concentration correlated positively with functional scores and current pain in areas overlapping with regions of increased GABAA receptor concentration. This study shows increased GABAA receptor concentration in FM, associated with pain symptoms and impaired function. The changes were widespread and not restricted to pain-processing regions. These findings suggest that the GABAergic system is altered, possibly indicating an imbalance between excitatory and inhibitory neurotransmission. Future studies should try to understand the nature of the dysregulation of the GABAergic system in FM and in other pain syndromes.

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABA A receptor concentration, an indirect marker of neuronal integrity measured with [ 18 F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABA A receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABA A receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABA A receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain., Significance Statement: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABA A receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABA A receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain., (Copyright © 2017 the authors 0270-6474/17/371091-12$15.00/0.)

Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [(18)F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (ρ = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo.

Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study's aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [(18)F]SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Converging preclinical, and human epidemiological, neuroimaging, and genetic evidence suggests a central role for dopamine neurotransmission in modulating pain perception and analgesia. Dysregulation in dopamine signaling may modulate the experience of pain both directly, by enhancing or diminishing the propagation of nociceptive signals, and indirectly, by influencing affective and cognitive processes, which affect the expectation, experience, and interpretation of nociceptive signals. Hypersensitivity to pain and high rates of comorbid chronic pain are common in disorders linked with deficits in dopamine system function, including disorders of mood and affect, substance abuse, and Parkinson disease. Hyposensitivity to pain, however, is common in patients with schizophrenia, which has been linked with excessive dopamine neurotransmission. Although patients are typically affected most by the primary symptoms of their disorders, alterations in pain perception may further increase the burden of their illness, compromising their quality of life. The present review focuses on this relationship, and discusses clinical and potential therapeutic implications for both patients with dopamine-related disorders and those with chronic pain syndromes., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)