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IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.
Chopra S, Giovanelli P, Alvarado-Vazquez PA, Alonso S, Song M, Sandoval TA, Chae CS, Tan C, Fonseca MM, Gutierrez S, Jimenez L, Subbaramaiah K, Iwawaki T, Kingsley PJ, Marnett LJ, Kossenkov AV, Crespo MS, Dannenberg AJ, Glimcher LH, Romero-Sandoval EA, Cubillos-Ruiz JR
(2019) Science 365:
MeSH Terms: Animals, Cells, Cultured, Cyclooxygenase 2, Dinoprostone, Endoribonucleases, Humans, Leukocytes, Mice, Mice, Inbred C57BL, Myeloid Cells, Pain, Postoperative, Promoter Regions, Genetic, Prostaglandin-E Synthases, Protein-Serine-Threonine Kinases, Signal Transduction, Unfolded Protein Response, Visceral Pain, X-Box Binding Protein 1
Show Abstract · Added March 12, 2020
Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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18 MeSH Terms
The Effects of Pain Severity, Pain Catastrophizing, Depression, and Exercise on Perceived Disability in Acute Low Back Pain Patients.
Salt E, Wiggins AT, Hooker Q, Crofford L, Rayens MK, Segerstrom S
(2018) Res Theory Nurs Pract 32: 436-448
MeSH Terms: Adult, Catastrophization, Cross-Sectional Studies, Depressive Disorder, Disabled Persons, Exercise, Female, Humans, Low Back Pain, Male, Middle Aged, Models, Psychological, Pain Measurement, Severity of Illness Index, Surveys and Questionnaires, Young Adult
Show Abstract · Added March 25, 2020
The effectiveness of cognitive treatments for low back pain, a prevalent and costly condition, are commonly based on the principles of the Cognitive Behavioral Model of Fear of Movement/(Re)injury. In this model, persons with a painful injury/experience who also engage in pain catastrophizing are most likely to avoid activity leading to disability. The validation of this model in patients with acute low back is limited. The purpose of this project was to examine the relationship of perceived disability with variables identified in the Cognitive Behavioral Model of Fear of Movement/(Re)injury such as, pain severity, pain catastrophizing, depression, and exercise in persons with acute low back pain. A multiple linear regression model was used to assess the association of perceived disability with pain severity, pain catastrophizing, depression, and exercise at baseline among subjects with acute low back pain ( = 44) participating in a randomized clinical trial to prevent transition to chronic low back pain. Controlling for age, the overall model was significant for perceived disability ([5, 35] = 14.2; < .001). Higher scores of pain catastrophizing ( = .003) and pain severity ( < .001) were associated with higher perceived disability levels. Exercise and depression were not significantly associated with perceived disability. The use of the Cognitive Behavioral Model of Fear of Movement/(Re)injury in acute LBP patients is appropriate; because this model is commonly used as rationale for the effectiveness of cognitive treatments, these findings have clinical relevance in the treatment of this condition.
© 2018 Springer Publishing Company, LLC.
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The association between endogenous opioid function and morphine responsiveness: a moderating role for endocannabinoids.
Bruehl S, Burns JW, Morgan A, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Kingsley PJ, Marnett L, Stone A, Patel S
(2019) Pain 160: 676-687
MeSH Terms: Adult, Analgesics, Opioid, Chronic Pain, Double-Blind Method, Endocannabinoids, Exercise, Female, Humans, Low Back Pain, Male, Middle Aged, Morphine, Naloxone, Opioid Peptides, Pain Measurement, Regression Analysis, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added April 12, 2019
We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.
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18 MeSH Terms
Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models.
Abney KK, Bubser M, Du Y, Kozek KA, Bridges TM, Linsdley CW, Daniels JS, Morrison RD, Wickman K, Hopkins CR, Jones CK, Weaver CD
(2019) ACS Chem Neurosci 10: 1294-1299
MeSH Terms: Analgesics, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Therapy, Combination, Formaldehyde, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, Hot Temperature, Humans, Male, Mice, Inbred C57BL, Morphine, Pain
Show Abstract · Added April 10, 2019
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.
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14 MeSH Terms
Growing Pains in Cardiovascular Genetics.
Roden DM
(2018) Circulation 138: 1206-1209
MeSH Terms: Athletes, Cardiovascular System, Extremities, Genetic Testing, Humans, Pain
Added March 24, 2020
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Posttraumatic stress disorder in interstitial cystitis/bladder pain syndrome: Relationship to patient phenotype and clinical practice implications.
McKernan LC, Johnson BN, Reynolds WS, Williams DA, Cheavens JS, Dmochowski RR, Crofford LJ
(2019) Neurourol Urodyn 38: 353-362
MeSH Terms: Adult, Chronic Pain, Comorbidity, Cystitis, Interstitial, Female, Humans, Incidence, Male, Middle Aged, Phenotype, Prevalence, Quality of Life, Stress Disorders, Post-Traumatic, Surveys and Questionnaires
Show Abstract · Added September 16, 2019
PURPOSE - The relationship between exposure to abuse and interstitial cystitis/bladder pain syndrome (IC/BPS) is well-documented. However, studies have yet to examine posttraumatic stress disorder (PTSD), which develops following exposure to trauma and worsens health outcomes in chronic pain. We aimed to assess the prevalence and impact of PTSD in patients with IC/BPS, including their relation to genitourinary symptom presentation and widespread pain phenotype.
MATERIALS AND METHODS - We recruited 202 participants with chronic pain from an academic medical center and classified 64 individuals as IC/BPS based on validated epidemiological criteria. Participants completed self-reported questionnaires assessing trauma exposure, PTSD symptoms, emotional distress, pain, and urinary symptoms. Wilcoxon rank-sum tests assessed study aims comparing IC/BPS to other chronic pain.
RESULTS - Although elevated, IC/BPS trauma exposure rates were equivalent to that of other chronic pain conditions in the sample. Despite this equivalence, in comparison, IC/BPS patients had significantly higher rates of PTSD symptoms, with 42% meeting provisional diagnostic criteria for PTSD. Among IC/BPS, those meeting provisional criteria for PTSD had significantly higher incidence of lifetime sexual abuse, childhood trauma, and presentations consistent with the widespread pain phenotype. In IC/BPS, there was no association between PTSD and genitourinary symptoms, but provisional PTSD was associated with more pain, emotional distress, and poorer quality of life.
CONCLUSIONS - We recommend that patients with IC/BPS and widespread pain have ongoing screening and monitoring of PTSD. We recommend using trauma-informed care practices with these patients to increase trust and safety, which could improve treatment compliance and follow-up.
© 2018 Wiley Periodicals, Inc.
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14 MeSH Terms
Differential cerebral hemometabolic responses to blood transfusions in adults and children with sickle cell anemia.
Juttukonda MR, Lee CA, Patel NJ, Davis LT, Waddle SL, Gindville MC, Pruthi S, Kassim AA, DeBaun MR, Donahue MJ, Jordan LC
(2019) J Magn Reson Imaging 49: 466-477
MeSH Terms: Adolescent, Adult, Age Factors, Anemia, Sickle Cell, Blood Transfusion, Brain, Cerebrovascular Circulation, Child, Female, Hematocrit, Hemodynamics, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Oximetry, Oxygen, Oxygen Consumption, Pain Management, Prospective Studies, Recurrence, Stroke, Young Adult
Show Abstract · Added March 24, 2020
BACKGROUND - Blood transfusions are administered to children and adults with sickle cell anemia (SCA) for secondary stroke prevention, or as treatment for recurrent pain crises or acute anemia, but transfusion effects on cerebral hemodynamics and metabolism are not well-characterized.
PURPOSE - To compare blood transfusion-induced changes in hemometabolic parameters, including oxygen extraction fraction (OEF) and cerebral blood flow (CBF), within and between adults and children with SCA.
STUDY TYPE - Prospective, longitudinal study.
SUBJECTS - Adults with SCA (n = 16) receiving simple (n = 7) or exchange (n = 9) transfusions and children with SCA (n = 11) receiving exchange transfusions were scanned once when hematocrit was near nadir and again within 7 days of transfusion. Adult controls without SCA or sickle trait (n = 7) were scanned twice on separate days.
FIELD STRENGTH/SEQUENCE - 3.0T T -weighted, T -weighted, and T -relaxation-under-spin-tagging (TRUST) imaging, and phase contrast angiography.
ASSESSMENT - Global OEF was computed as the relative difference between venous oxygenation (from TRUST) and arterial oxygenation (from pulse oximetry). Global CBF was computed as total blood flow to the brain normalized by intracranial tissue volume.
STATISTICAL TESTS - Hemometabolic variables were compared using two-sided Wilcoxon signed-rank tests; associations were analyzed using two-sided Spearman's correlation testing.
RESULTS - In adults with SCA, posttransfusion OEF = 0.38 ± 0.05 was lower (P = 0.001) than pretransfusion OEF = 0.45 ± 0.09. A change in OEF was correlated with increases in hematocrit (P = 0.02; rho = -0.62) and with pretransfusion hematocrit (P = 0.02; rho = 0.65). OEF changes after transfusion were greater (P = 0.002) in adults receiving simple versus exchange transfusions. Posttransfusion CBF = 77.7 ± 26.4 ml/100g/min was not different (P = 0.27) from pretransfusion CBF = 82.3 ± 30.2 ml/100g/min. In children with SCA, both posttransfusion OEF = 0.28 ± 0.04 and CBF = 76.4 ± 26.4 were lower than pretransfusion OEF = 0.36 ± 0.06 (P = 0.004) and CBF = 96.4 ± 16.5 (P = 0.004).
DATA CONCLUSION - Cerebral OEF reduces following transfusions in adults and children with SCA. CBF reduces following transfusions more often in children compared to adults, indicating that vascular reserve capacity may remain near exhaustion posttransfusion in many adults.
LEVEL OF EVIDENCE - 2 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;49:466-477.
© 2018 International Society for Magnetic Resonance in Medicine.
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Characterization and development of SAPP as a specific peptidic inhibitor that targets Porphyromonas gingivalis.
Ho MH, Lamont RJ, Chazin WJ, Chen H, Young DF, Kumar P, Xie H
(2018) Mol Oral Microbiol 33: 430-439
MeSH Terms: Adhesins, Bacterial, Bacterial Adhesion, Biofilms, Cell Membrane, Cysteine Endopeptidases, Dental Plaque, Fibroblasts, Gingipain Cysteine Endopeptidases, Humans, Peptides, Periodontitis, Porphyromonas gingivalis, Virulence
Show Abstract · Added March 26, 2019
Porphyromonas gingivalis is a keystone bacterium in the oral microbial communities that elicits a dysbiosis between the microbiota and the host. Therefore, inhibition of this organism in dental plaques has been one of the strategies for preventing and treating chronic periodontitis. We previously identified a Streptococcal ArcA derived Anti-P gingivalils Peptide (SAPP) that in vitro, is capable of repressing the expression of several virulence genes in the organism. This leads to a significant reduction in P gingivalis virulence potential, including its ability to colonize on the surface of Streptococcus gordonii, to invade human oral epithelial cells, and to produce gingipains. In this study, we showed that SAPP had minimal cytotoxicity to human oral keratinocytes and gingival fibroblasts. We observed that SAPP directly bound to the cell surface of P gingivalis, and that alterations in the sequence at the N-terminus of SAPP diminished its abilities to interact with P gingivalis cells and repressed the expression of virulence genes. Most strikingly, we demonstrated using an ex-vivo assay that besides its inhibitory activity against P gingivalis colonization, SAPP could also reduce the levels of several other oral Gram-negative bacteria strongly associated with periodontitis in multispecies biofilms. Our results provide a platform for the development of SAPP-targeted therapeutics against chronic periodontitis.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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13 MeSH Terms
Postoperative Opiate Use in Urological Patients: A Quality Improvement Study Aimed at Improving Opiate Disposal Practices.
Cabo J, Hsi RS, Scarpato KR
(2019) J Urol 201: 371-376
MeSH Terms: Analgesics, Opioid, Humans, Pain Management, Pain, Postoperative, Patient Education as Topic, Postoperative Period, Prescription Drug Misuse, Quality Improvement, Retrospective Studies, Tennessee, Urologic Surgical Procedures
Show Abstract · Added February 26, 2019
PURPOSE - We aimed to determine trends in postoperative opiate management among urological patients, identify associations with opiate keeping and foster appropriate opiate disposal after surgery via introduction of an educational handout.
MATERIALS AND METHODS - We retrospectively analyzed opiate practices in 68 patients who had undergone urological surgery. In a separate consecutive cohort of 59 patients we distributed a handout detailing FDA (Food and Drug Administration) approved disposal methods. Patient opiate obtainment, use and disposal were assessed via telephone interviews with prescription filling data verified using the Tennessee CSMD (Controlled Substances Monitoring Database). Opiate keeping was defined as possessing any opiates more than 3 weeks after surgery or more than 4 times the duration of the postoperative prescription, whichever was longer.
RESULTS - Opiate keeping was observed in 41 patients (72%) in our initial cohort. Of these patients 68% left the medication unsecured at home. Major barriers to opiate disposal included concern for return of disease specific pain in 44% of patients and unrelated pain in 29%. As assessed on a short test, opiate keepers were less knowledgeable about safe disposal practices compared to nonkeepers (72% vs 85%, p = 0.005). Among opiate keepers there was an improvement in knowledge scores after the intervention (66% to 77%, p = 0.03). When comparing pre-education to post-education, there was no detectable improvement in the rate of opiate keeping (72% vs 68%, p = 0.66) or proper disposal (9% vs 8%, p = 1.0).
CONCLUSIONS - Opiate keeping is common following urological surgery and a major barrier to disposal is concern for the return of disease specific pain. Future interventions aimed at limiting opiate keeping should combine evidence-based prescription practices and targeted patient education.
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The Relationship Between Life Purpose With Depression and Disability in Acute Low Back Pain Patients.
Salt E, Wiggins AC, Rayens MK, Johnson R, Hardy JK, Segerstrom S, Crofford LJ
(2018) Orthop Nurs 37: 287-291
MeSH Terms: Adult, Aged, Depression, Disabled Persons, Exercise Therapy, Female, Humans, Linear Models, Low Back Pain, Male, Middle Aged, Pain Measurement, Treatment Outcome
Show Abstract · Added March 25, 2020
BACKGROUND - Life purpose in acute low back pain patients is not well described in published literature.
METHODS/PURPOSE - We used linear regression models to describe the relationship of life purpose with perceived functional disability and depression in persons with acute low back pain (N = 42) participating in a randomized clinical trial to prevent transition to chronic low back pain.
RESULTS - In our predominantly female sample (81.8%) with a mean age of 53 years (SD = 11.6 years), 52% worked full-time. Adjusting for age, gender, and working status, life purpose was a significant correlate of depression (p = .007). For every 10-unit increase in life purpose score, the estimated depression score decreased by almost 2.5 points. A significant relationship between life purpose and perceived functional disability was not identified.
CONCLUSION - Life purpose likely is a modifiable risk factor for depression in acute low back pain patients.
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