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G protein-gated inwardly rectifying potassium (GIRK) channels are potassium-selective ion channels. As their name suggests, GIRK channels are effectors of G G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of G-coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of opioid analgesics which act predominantly through G-coupled, opioid-activated GPCRs (e.g., μ-opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in pain pathways and as effectors of opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce analgesic efficacy and/or augment the analgesic efficacy morphine, an opioid receptor agonist capable of activating μ-opioid receptors as well as other opioid receptor subtypes. In the present study, we demonstrate that the small-molecule GIRK activator, VU0466551, has analgesic effects when dosed alone or in combination with submaximally effective doses of morphine.
PURPOSE - We sought to determine whether women with overactive bladder who required third line therapy would demonstrate greater central sensitization, indexed by temporal summation to heat pain stimuli, than those with overactive bladder.
MATERIALS AND METHODS - We recruited 39 women with overactive bladder from the urology clinic who were planning to undergo interventional therapy for medication refractory overactive bladder with onabotulinumtoxinA bladder injection or sacral neuromodulation. We also recruited 55 women with overactive bladder who were newly seen at our urology clinic or who responded to advertisements for study participation. Participants underwent quantitative sensory testing using a thermal temporal summation protocol. The primary study outcome was the degree of temporal summation as reflected in the magnitude of positive slope of the line fit to the series of 10 stimuli at a 49C target temperature. We compared the degree of temporal summation between the study groups using linear regression.
RESULTS - Women in the group undergoing third line therapy showed significantly higher standardized temporal summation slopes than those in the nontreatment group (β = 1.57, 95% CI 0.18-2.96, t = 2.25, p = 0.027). On exploratory analyses a history of incontinence surgery or hysterectomy was associated with significantly greater temporal summation.
CONCLUSIONS - In this study the degree of temporal summation was elevated in women undergoing third line overactive bladder therapy compared to women with overactive bladder who were not undergoing that therapy. These findings suggest there may be pathophysiological differences, specifically in afferent nerve function and processing, in some women with overactive bladder.
Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
This study addresses one long-standing question of whether functional separations are preserved for somatosensory modalities of touch, heat, and cold nociception within primate primary somatosensory (S1) cortex. This information is critical for understanding how the nature of pain is represented in the primate brain. Using a combination of submillimeter-resolution fMRI and microelectrode local field potential (LFP) and spike recordings, we identified spatially segregated cortical zones for processing touch and nociceptive heat and cold stimuli in somatotopically appropriate areas 3a, 3b, 1, and 2 of S1 in male monkeys. The distances between zones were comparable (∼3.4 mm) across stimulus modalities (heat, cold, and tactile), indicating the existence of uniform, modality-specific modules. Stimulus-evoked LFP maps validated the fMRI maps in areas 3b and 1. Isolation of heat and cold nociceptive neurons from the fMRI zones confirmed the validity of using fMRI to probe nociceptive regions and circuits. Resting-state fMRI analysis revealed distinct intrinsic functional circuits among functionally related zones. We discovered distinct modular structures and networks for thermal nociception within S1 cortex, a finding that has significant implications for studying chronic pain syndromes and guiding the selection of neuromodulation targets for chronic pain management. Primate S1 subregions contain discrete heat and cold nociceptive modules. Modules with the same properties exhibit strong functional connection. Nociceptive fMRI response coincides with LFP and spike activities of nociceptive neurons. Functional separation of heat and cold pain is retained within primate S1 cortex.
Copyright © 2018 the authors 0270-6474/18/381774-14$15.00/0.
There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-β-melibioside (β-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the β-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-β-maltoside (β-DDM). β-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into β-DDMB yielded activities that were 40% higher than those of DAGK purified into β-DDM. β-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. β-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.
BACKGROUND - People with Alzheimer's disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD.
OBJECTIVE - The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD.
METHODS - Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics.
RESULTS - There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p = 0.004, unpleasantness: p < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen's d = 0.72, p = 0.051, moderate: Cohen's d = 0.80, p = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen's d = 0.80, p = 0.072, moderate: Cohen's d = 1.32, p = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs = 0.29 and rs = 0.20 respectively, p > 0.05).
CONCLUSIONS - Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.
The Complex II homolog quinol:fumarate reductase (QFR, FrdABCD) catalyzes the interconversion of fumarate and succinate at a covalently attached FAD within the FrdA subunit. The SdhE assembly factor enhances covalent flavinylation of Complex II homologs, but the mechanisms underlying the covalent attachment of FAD remain to be fully elucidated. Here, we explored the mechanisms of covalent flavinylation of the QFR FrdA subunit. Using a Δ strain, we show that the requirement for the assembly factor depends on the cellular redox environment. We next identified residues important for the covalent attachment and selected the FrdA residue, which contributes to proton shuttling during fumarate reduction, for detailed biophysical and structural characterization. We found that QFR complexes containing FrdA have a structure similar to that of the WT flavoprotein, but lack detectable substrate binding and turnover. In the context of the isolated FrdA subunit, the anticipated assembly intermediate during covalent flavinylation, FrdA variants had stability similar to that of WT FrdA, contained noncovalent FAD, and displayed a reduced capacity to interact with SdhE. However, small-angle X-ray scattering (SAXS) analysis of WT FrdA cross-linked to SdhE suggested that the FrdA residue is unlikely to contribute directly to the FrdA-SdhE protein-protein interface. We also found that no auxiliary factor is absolutely required for flavinylation, indicating that the covalent flavinylation is autocatalytic. We propose that multiple factors, including the SdhE assembly factor and bound dicarboxylates, stimulate covalent flavinylation by preorganizing the active site to stabilize the quinone-methide intermediate.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone (17α-OH-progesterone) to 11-deoxycortisol. More than 100 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17α-OH-progesterone). We found that the 17α-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants () for four variants were 37-13,000-fold higher than for WT P450 21A2. Cytochrome , which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (≥ 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21--progesterone, indicating that C-H bond breaking is a rate-limiting step over a 10-fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Pain assessments typically depend on self-report of the pain experience. Yet, in individuals with autism spectrum disorders, this can be an unreliable due to communication difficulties. Importantly, observations of behavioral hypo- and hyperresponsivity to pain suggest altered pain sensitivity in autism spectrum disorder. Neuroimaging may provide insight into mechanisms underlying pain behaviors. The neural pain signature reliably responds to painful stimulation and is modulated by other outside regions, affecting the pain experience. In this first functional magnetic resonance imaging study of pain in autism spectrum disorder, we investigated neural responses to pain in 15 adults with autism spectrum disorder relative to a typical comparison group (n = 16). We explored temporal and spatial properties of the neural pain signature and its modulators during sustained heat pain. The two groups had indistinguishable pain ratings and neural pain signature responses during acute pain; yet, we observed strikingly reduced neural pain signature response in autism spectrum disorder during sustained pain and after stimulus offset. The posterior cingulate cortex, a neural pain signature modulating region, mirrored this late signal reduction in autism spectrum disorder. Intact early responses, followed by diminished late responses to sustained pain, may reflect altered pain coping or evaluation in autism spectrum disorder. Evidence of a dichotomous neural response to initial versus protracted pain may clarify the coexistence of both hypo- and hyperresponsiveness to pain in autism spectrum disorder.
BACKGROUND - It is currently unknown why people with Alzheimer's disease (AD) receive less pain medication and report pain less frequently.
OBJECTIVE - The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures.
METHODS - Controls (n = 23, 13 = female) and age-matched people with AD (n = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions of pain, descending pain modulation, and the default mode network.
RESULTS - People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only.
CONCLUSIONS - While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration.
INTRODUCTION - This study sought to provide a preliminary assessment of whether spinally mediated afferent hyperactivity (i.e., central sensitization) might contribute to manifestations of overactive bladder syndrome (OAB) in women as indexed by elevated temporal summation of evoked heat pain stimuli.
METHODS - We recruited 20 adult women with OAB who were planning to undergo interventional therapy for OAB with either onabotulinumtoxinA injection or sacral neuromodulation and 23 healthy controls without OAB symptoms to undergo quantitative sensory testing with cutaneous thermal pain temporal summation. The primary study outcome was the degree of temporal summation, as reflected in the magnitude of positive slope of the line fitted to the series of 10 stimuli at the 49°C target temperatures. Linear regression and analysis of covariance were utilized to compare the degree of temporal summation between study groups.
RESULTS - The standardized slope of temporal summation trials for women with OAB was significantly higher than for controls (β = 3.43, 95% confidence interval = 0.6-6.2, P = 0.017). The adjusted means ±SE of the standardized temporal summation slopes for the full OAB and control groups were 3.0 ± 0.5 (95% confidence interval = 2.0, 4.1) and 1.7 ± 0.5 (95% confidence interval = 0.7, 2.7), respectively.
CONCLUSION - In this preliminary study, we demonstrated that women with OAB refractory to primary and secondary therapies exhibited greater thermal cutaneous temporal summation than women without OAB symptoms. This suggests that central sensitization, indexed by temporal summation, may be an underlying factor contributing to OAB in some women. Neurourol. Urodynam. 36:1108-1112, 2017. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.