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1.
Pain Manag ; 2021 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-34431328

RESUMEN

Aim: Determine if dietary patterns affect risk of pain. Methods: Data from 16,061 participants (55.4% females, 32.3% Black, age 65 ± 9 years) in the REGARDS study were categorized based on the adherence to previous dietary patterns reflecting the prevalent foods within each (convenience, alcohol/salads, plant-based, sweets/fats and 'southern'). A modified Poisson regression model was used to determine whether dietary patterns were associated with relative risk (RR) of pain. Results: High adherence to 'Southern' dietary pattern was associated with a 41% (95% CI: 23, 61%) increase in RR of pain. High adherence to a plant-based dietary pattern showed a 22% (95% CI: 11, 31%) decrease in the RR of pain. Conclusion: Poor quality dietary patterns increase the RR of pain, while plant-based patterns lowered the RR. Diet patterns should be incorporated into medical history.

2.
J Behav Med ; 44(6): 811-821, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34106368

RESUMEN

Individuals with chronic low back pain (cLBP) frequently report sleep disturbances. Living in a neighborhood characterized by low-socioeconomic status (SES) is associated with a variety of negative health outcomes, including poor sleep. Whether low-neighborhood SES exacerbates sleep disturbances of people with cLBP, relative to pain-free individuals, has not previously been observed. This study compared associations between neighborhood-level SES, pain-status (cLBP vs. pain-free), and daily sleep metrics in 117 adults (cLBP = 82, pain-free = 35). Neighborhood-level SES was gathered from Neighborhood Atlas, which provides a composite measurement of overall neighborhood deprivation (e.g. area deprivation index). Individuals completed home sleep monitoring for 7-consecutive days/nights. Neighborhood SES and pain-status were tested as predictors of actigraphic sleep variables (e.g., sleep efficiency). Analyses revealed neighborhood-level SES and neighborhood-level SES*pain-status interaction significantly impacted objective sleep quality. These findings provide initial support for the negative impact of low neighborhood-level SES and chronic pain on sleep quality.

3.
BMC Musculoskelet Disord ; 22(1): 429, 2021 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-33971876

RESUMEN

BACKGROUND: Biopsychosocial factors above and beyond pathoanatomical changes likely contribute to the severity of chronic low back pain. A pro-nociceptive endogenous pain modulatory balance (↓inhibition and ↑facilitation) may be an important contributor to chronic low back pain severity and physical function; however, additional research is needed to address this possibility. The objective of this study was to determine whether quantitative sensory tests of endogenous pain inhibition and facilitation prospectively predict movement-evoked pain and cLBP severity self-reported on a validated questionnaire. METHODS: One hundred thirty-four individuals with chronic low back pain were enrolled in this two-session study. During the first study session, temporal summation of mechanical pain and conditioned pain modulation were assessed at the lumbar spine to determine endogenous pain facilitation and inhibition, respectively. One week later, participants returned for a second study session whereby they reported their pain severity and pain interference using the Brief Pain Inventory-Short Form. Movement-evoked pain and physical function capacity were assessed upon completion of the balance, walking, and transition from sit to stand tests of the Short Physical Performance Battery. RESULTS: Temporal summation of mechanical pain, but not conditioned pain modulation, significantly and prospectively predicted greater movement-evoked pain and poorer physical function on the Short Physical Performance Battery. Neither temporal summation nor conditioned pain modulation were significantly related to self-reported pain severity or pain interference on the Brief Pain Inventory-Short Form. CONCLUSIONS: Findings suggest that a pro-nociceptive pain modulatory balance characterized by enhanced pain facilitation may be an important driver of movement-evoked pain severity and poor physical function in individuals with chronic low back pain.


Asunto(s)
Dolor Crónico , Dolor de la Región Lumbar , Adulto , Dolor Crónico/diagnóstico , Humanos , Dolor de la Región Lumbar/diagnóstico , Vértebras Lumbares , Movimiento , Dimensión del Dolor , Umbral del Dolor , Encuestas y Cuestionarios
4.
Neurobiol Pain ; 8: 100053, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33204899

RESUMEN

Obesity is a global concern and affects millions of Americans who consume poor-quality diets. Diets directly affect the gut microbiota, which can have subsequent effects on inflammation and contribute to other chronic states. Previously we have shown that a Standard American Diet (SAD) increased immune cell activation and prolonged recovery and that a beneficial diet could reduce these negative effects. Here, male and female mice were given access to regular chow (REG), SAD, our Anti-Inflammatory Diet (AID) or a combination of SAD and AID. This latter group was modeled on the commonplace dietary pattern of healthy eating during the week (AID: Monday-Friday) and relaxed eating patterns on the weekend (SAD: Saturday-Sunday). After 14 weeks of diet consumption and an inflammatory injury, we found that the SAD prolonged and the AID promoted recovery. However, recovery was significantly delayed in those mice consuming the AID-SAD, regardless of weekly healthy diet access. In addition, fecal samples taken during the study revealed dramatic differences in microbial community composition, relative abundance of abundant bacterial phyla and alpha diversity. These data confirm the impact of diet on gut microbiota and suggest a relation between abundance of specific bacterial taxa and susceptibility to prolonged recovery from injury.

5.
Pain Ther ; 9(2): 487-498, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33085012

RESUMEN

Chronic pain is highly prevalent in the United States, impacting 28.4% of the adult population, or 69.6 million people, as of 2016. Chronic pain is often associated with anxiety, depression, and restrictions in mobility and daily activities, substantially reducing quality of life. Analgesics, especially opioids, are one of the primary pharmaceutical treatment methods for chronic pain. However, prescription opioid misuse and abuse has become increasingly prevalent and concerning, prompting the need for research into alternative treatment methods which avoid the side effects of traditional treatments. Chronic pain is, in part, thought to be the result of oxidative stress and inflammation, and clinical research has indicated links between these conditions and diet. Thus, dietary interventions are a particularly promising therapeutic treatment for chronic pain, with numerous studies suggesting that diet has a noticeable effect on pain as far down as the cellular level. In this review article, data from a number of clinical trials assessing the effect of three diets-antioxidant-rich, low-carbohydrate, and Mediterranean-on oxidative stress and inflammation is compiled and discussed in the context of chronic pain. Clinical data suggests that low-carbohydrate diets and Mediterranean diets both are especially promising dietary interventions.

6.
Front Immunol ; 11: 590794, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33123173

RESUMEN

Nearly 70% of adults in the US are currently overweight or obese. Despite such high prevalence, the impact of obesity on antitumor immunity and immunotherapy outcomes remains incompletely understood, particularly in patients with breast cancer. Here, we addressed these gaps in knowledge using two murine models of breast cancer combined with diet-induced obesity. We report that obesity increases CXCL1 concentrations in the mammary tumor microenvironment, driving CXCR2-mediated chemotaxis and accumulation of granulocytic myeloid-derived suppressor cells (G-MDSCs) expressing Fas ligand (FasL). Obesity simultaneously promotes hyperactivation of CD8 tumor-infiltrating lymphocytes (TILs), as evidenced by increased expression of CD44, PD-1, Ki-67, IFNγ, and the death receptor Fas. Accordingly, G-MDSCs induce Fas/FasL-mediated apoptosis of CD8 T cells ex vivo and in vivo. These changes promote immunotherapy resistance in obese mice. Disruption of CXCR2-mediated G-MDSC chemotaxis in obese mice is sufficient to limit intratumoral G-MDSC accumulation and improve immunotherapy outcomes. The translational relevance of our findings is demonstrated by transcriptomic analyses of human breast tumor tissues, which reveal positive associations between CXCL1 expression and body mass index, poor survival, and a MDSC gene signature. Further, this MDSC gene signature is positively associated with FASLG expression. Thus, we have identified a pathway wherein obesity leads to increased intratumoral CXCL1 concentrations, which promotes CXCR2-mediated accumulation of FasL+ G-MDSCs, resulting in heightened CD8 TIL apoptosis and immunotherapy resistance. Disruption of this pathway may improve immunotherapy outcomes in patients with breast cancer and obesity.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Mamarias Experimentales/inmunología , Células Supresoras de Origen Mieloide/inmunología , Obesidad/inmunología , Adenoviridae/genética , Animales , Apoptosis , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Inmunoterapia , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/terapia , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/administración & dosificación , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/inmunología
7.
J Pain Res ; 13: 829-835, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32425587

RESUMEN

Background: Sex differences in pain sensitivity have been well documented, such that women often report greater sensitivity than men. However, clinical reports highlighting sex differences often equate gender and sex. This is a particularly critical oversight for those whose gender identity is different than their genetic sex. Methods: This preliminary study sets to analyze differences in pain responses between cisgender and transgender individuals living with HIV and chronic pain. A total of 51 African-American participants (24 cisgender men, 20 cisgender women, 7 transgender women) with similar socioeconomic status were recruited. Genetic sex, gender identity, depression and anxiety, pain severity, pain interference and pain-related stigma were recorded. Participants also completed a quantitative sensory testing battery to assess pain in response to noxious heat and mechanical stimuli. Results: Transgender women and cisgender women demonstrated a greater magnitude of temporal summation for heat pain stimuli or mechanical stimuli compared to cisgender men. Specifically, transgender women reported greater mechanical summation than either cisgender women or cisgender men. Transgender women and cisgender women similarly reported greater chronic pain severity compared to cisgender men. Conclusion: These data support the notion that gender identity may play a more significant role in pain sensation than genetic sex. These results further maintain that not only gender identity and genetic sex are distinct variables but that treatment should be based on identity as opposed to genetic sex.

8.
Front Neurosci ; 14: 385, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32425750

RESUMEN

Introduction: Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects. Methods: Groups of female Sprague-Dawley rats received unilateral trunk (L5 vertebral level) injections (50 µl) of either vehicle (phosphate-buffer solution, PBS; VEH) or nerve growth factor (NGF; 0.8 µM) on Days 0 and 5 with or without daily L5 SM (VEH, NGF, VEH + SM, VEH + SM). Daily passive SM (10 min) was delivered by a feedback motor (1.2 Hz, 0.9N) from Days 1 to 12. Changes in pain assays were determined for mechanical and thermal reflexive behavior, exploratory behavior (open field events) and spontaneous pain behavior (rat grimace scale). On Day 12, lumbar (L1-L6) dorsal root ganglia (DRG) were harvested bilaterally and calcitonin gene-related peptide (CGRP) positive immunoreactive neurons were quantified from 3 animals (1 DRG tissue section per segmental level) per experimental group. Results: NGF induced bilateral trunk (left P = 0.006, right P = 0.001) mechanical hyperalgesia and unilateral hindpaw allodynia (P = 0.006) compared to the vehicle group by Day 12. Additionally, we found for the first time that NGF animals demonstrated decreased exploratory behaviors (total distance traveled) and increased grimace scale scoring compared to the VEH group. Passive SM prevented this development of local (trunk) mechanical hyperalgesia and distant (hindpaw) allodynia, and normalized grimace scale scores. NGF increased CGRP positive immunoreactive neurons in ipsilateral lumbar DRGs compared to the VEH group ([L1]P = 0.02; [L2]P = 0.007) and SM effectively negated this increase in pain-related neuropeptide CGRP expression. Conclusion: SM prevents the development of local (trunk) NGF-induced mechanical hyperalgesia and distant (hindpaw) allodynia, in part, through attenuation of CGRP expression in lumbar DRG sensory neurons. NGF decreases rat exploratory behavior and increases spontaneous pain for which passive SM acts to mitigate these pain-related behavioral changes. These initial study findings suggest that beginning daily SM soon after injury onset might act to minimize or prevent the development of LBP by reducing production of pain-related neuropeptides.

9.
J Immunother Cancer ; 8(2)2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33427691

RESUMEN

BACKGROUND: Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes. METHODS: We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, 'BMI' ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString. RESULTS: With obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1ß in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors. CONCLUSIONS: We find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1ß levels, highlighting the need for continued study of this critical issue.


Asunto(s)
Inmunoterapia/métodos , Neoplasias Renales/tratamiento farmacológico , Obesidad/complicaciones , Animales , Femenino , Humanos , Neoplasias Renales/inmunología , Masculino , Ratones , Estudios Prospectivos , Estudios Retrospectivos
10.
Pain Med ; 21(1): 150-160, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30865775

RESUMEN

OBJECTIVE: Osteoarthritis is the most prominent form of arthritis, affecting approximately 15% of the population in the United States. Knee osteoarthritis (KOA) has become one of the leading causes of disability in older adults. Besides knee replacement, there are no curative treatments for KOA, so persistent pain is commonly treated with opioids, acetaminophen, and nonsteroidal anti-inflammatory drugs. However, these drugs have many unpleasant side effects, so there is a need for alternative forms of pain management. We sought to test the efficacy of a dietary intervention to reduce KOA. DESIGN: A randomized controlled pilot study to test the efficacy of two dietary interventions. SUBJECTS: Adults 65-75 years of age with KOA. METHODS: Participants were asked to follow one of two dietary interventions (low-carbohydrate [LCD], low-fat [LFD]) or continue to eat as usual (control [CTRL]) over 12 weeks. Functional pain, self-reported pain, quality of life, and depression were assessed every three weeks. Serum from before and after the diet intervention was analyzed for oxidative stress. RESULTS: Over a period of 12 weeks, the LCD reduced pain intensity and unpleasantness in some functional pain tasks, as well as self-reported pain, compared with the LFD and CTRL. The LCD also significantly reduced oxidative stress and the adipokine leptin compared with the LFD and CTRL. Reduction in oxidative stress was related to reduced functional pain. CONCLUSIONS: We present evidence suggesting that oxidative stress may be related to functional pain, and lowering it through our LCD intervention could provide relief from pain and be an opioid alternative.


Asunto(s)
Dieta Baja en Carbohidratos/métodos , Dieta con Restricción de Grasas/métodos , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/dietoterapia , Dolor/etiología , Anciano , Femenino , Humanos , Masculino , Estrés Oxidativo/fisiología , Manejo del Dolor/métodos , Proyectos Piloto , Resultado del Tratamiento
11.
Neuropsychopharmacology ; 43(6): 1445-1456, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29362511

RESUMEN

Whereas cortical GAD67 reduction and subsequent GABA level decrease are consistently observed in schizophrenia and depression, it remains unclear how these GABAergic abnormalities contribute to specific symptoms. We modeled cortical GAD67 reduction in mice, in which the Gad1 gene is genetically ablated from ~50% of cortical and hippocampal interneurons. Mutant mice showed a reduction of tissue GABA in the hippocampus and cortex including mPFC, and exhibited a cluster of effort-based behavior deficits including decreased home-cage wheel running and increased immobility in both tail suspension and forced swim tests. Since saccharine preference, progressive ratio responding to food, and learned helplessness task were normal, such avolition-like behavior could not be explained by anhedonia or behavioral despair. In line with the prevailing view that dopamine in anterior cingulate cortex (ACC) plays a role in evaluating effort cost for engaging in actions, we found that tail-suspension triggered dopamine release in ACC of controls, which was severely attenuated in the mutant mice. Conversely, ACC dopamine release by progressive ratio responding to reward, during which animals were allowed to effortlessly perform the nose-poking, was not affected in mutants. These results suggest that cortical GABA reduction preferentially impairs the effort-based behavior which requires much effort with little benefit, through a deficit of ACC dopamine release triggered by high-effort cost behavior, but not by reward-seeking behavior. Collectively, a subset of negative symptoms with a reduced willingness to expend costly effort, often observed in patients with schizophrenia and depression, may be attributed to cortical GABA level reduction.


Asunto(s)
Corteza Cerebral/metabolismo , Glutamato Descarboxilasa/deficiencia , Hipocampo/metabolismo , Interneuronas/metabolismo , Motivación/fisiología , Ácido gamma-Aminobutírico/deficiencia , Animales , Reacción de Prevención/fisiología , Epilepsia/metabolismo , Femenino , Glutamato Descarboxilasa/genética , Masculino , Ratones Noqueados , Actividad Motora/fisiología , Fenotipo , Recompensa , Conducta Sexual Animal/fisiología , Conducta Social , Transmisión Sináptica/fisiología , Técnicas de Cultivo de Tejidos
12.
Scand J Pain ; 17: 316-324, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28927908

RESUMEN

BACKGROUND AND AIMS: Obesity is a significant health concern in the Western world and the presence of comorbid conditions suggests an interaction. The overlapping distributions of chronic pain populations and obesity suggests that an interaction may exist. Poor quality diet (high carbohydrates, saturated fats, omega-6 polyunsaturated fatty acids) can lead to increased adiposity which can activate immune cells independent of the activating effect of the diet components themselves. This dual action can contribute to chronic inflammation that may alter susceptibility to chronic pain and prolong recovery from injury. However, traditional examinations of diet focus on high-fat diets that often contain a single source of fat, that is not reflective of an American diet. Thus, we examined the impact of a novel human-relevant (high-carbohydrate) American diet on measures of pain and inflammation in rats, as well as the effect on recovery and immune cell activation. METHODS: We developed a novel, human-relevant Standard American Diet (SAD) to better model the kilocalorie levels and nutrient sources in an American population. Male and female rats were fed the SAD over the course of 20 weeks prior to persistent inflammatory pain induction with Complete Freund's Adjuvant (CFA). Mechanical and thermal sensitivity were measured weekly. Spontaneous pain, open field locomotion and blood glucose levels were measured during diet consumption. Body composition was assessed at 20 weeks. Following full recovery from CFA-induced hypersensitivity, blood was analyzed for inflammatory mediators and spinal cords were immunohistochemically processed for microglial markers. RESULTS: Chronic consumption of the SAD increased fat mass, decreased lean mass and reduce bone mineral density. SAD-fed rats had increased leptin levels and pro-inflammatory cytokines in peripheral blood serum. Following CFA administration, mechanical sensitivity was assessed and recovery was delayed significantly in SAD-fed animals. Sex differences in the impact of the SAD were also observed. The SAD increased body weight and common T-cell related inflammatory mediators in female, but not male, animals. In males, the SAD had a greater effect on bone mineral density and body composition. Long-term consumption of the SAD resulted in elevated microglial staining in the dorsal horn of the spinal cord, but no sex differences were observed. CONCLUSIONS: We demonstrate the negative effects of an American diet on physiology, behavior and recovery from injury. SAD consumption elevated pro-inflammatory mediators and increased microglial activation in the spinal cord. While there were sex differences in weight gain and inflammation, both sexes showed prolonged recovery from injury. IMPLICATIONS: These data suggest that poor quality diet may increase susceptibility to chronic pain due to persistent peripheral and central immune system activation. Furthermore, consumption of a diet that is high in carbohydrates and omega-6 polyunsaturated fatty acid is likely to lead to protracted recovery following trauma or surgical procedures. These data suggest that recovery of a number of patients eating a poor quality diet may be expedited with a change in diet to one that is healthier.


Asunto(s)
Tejido Adiposo , Conducta Animal/fisiología , Glucemia , Densidad Ósea , Dieta Occidental/efectos adversos , Inflamación , Microglía/inmunología , Dolor/inmunología , Médula Espinal/inmunología , Animales , Citocinas/sangre , Femenino , Inflamación/sangre , Inflamación/complicaciones , Inflamación/etiología , Inflamación/inmunología , Leptina/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Factores Sexuales
13.
J Clin Invest ; 127(9): 3353-3366, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-28783046

RESUMEN

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.


Asunto(s)
Dolor Crónico/metabolismo , Epirregulina/genética , Epirregulina/fisiología , Receptores ErbB/fisiología , Adolescente , Adulto , Animales , Conducta Animal , Estudios de Casos y Controles , Estudios de Cohortes , Drosophila melanogaster , Femenino , Humanos , Hiperalgesia/metabolismo , Inflamación , Ligandos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Mutación , Neuronas/metabolismo , Manejo del Dolor , Fosforilación , Polimorfismo de Nucleótido Simple , Unión Proteica , Transducción de Señal , Adulto Joven
14.
J Acquir Immune Defic Syndr ; 75(4): e99-e103, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28328552

RESUMEN

BACKGROUND: The pathophysiology of chronic pain experienced by people living with HIV (PLWH) in the current antiretroviral treatment era is poorly understood. We sought to investigate the relationship between inflammation and chronic pain in PLWH. We hypothesized that, among PLWH who have undetectable HIV viral loads, those with chronic multisite pain (CMP) would have higher levels of circulating pain-related inflammatory markers than those without chronic pain. SETTING: This study was conducted at the University of Alabama at Birmingham's Center for AIDS Research Network of Integrated Clinical System site. METHODS: We compared inflammatory markers in 70 PLWH with CMP and 70 PLWH without chronic pain. Custom multiplex human inflammatory assays were completed on banked plasma specimens to measure cytokines commonly associated with chronic inflammatory pain: interleukin 1ß (IL-1ß), eotaxin, IL-15, IL-6, tumor necrosis factor α, and leptin. Logistic regression models were built using group status (CMP vs no pain) as the outcome variable, with each cytokine as independent variables and age, sex, substance use, and prescribed opioid medications as covariates. RESULTS: Participants were mostly men (71%); 53% were 50 years or older. The most common sites of pain were low back (86%), hands/feet (81%), and knee (66%). Median CD4 T-cell count was 676 cells per milliliter. IL-1ß was significantly higher in the CMP group than in the individuals without chronic pain (odds ratio: 1.35, 95% confidence interval: 1.01 to 1.82, P < 0.05). Eotaxin, IL-15, IL-6, tumor necrosis factor α, and leptin were not significantly different between groups. CONCLUSIONS: We found that PLWH who also have CMP have significantly higher levels of IL-1ß than PLWH who do not have any pain. Future work on the role of IL-1ß on chronic pain pathogenesis in this population may inform novel approaches to chronic pain management.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Dolor Crónico/complicaciones , Dolor Crónico/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Interleucina-1beta/inmunología , Alabama , Dolor Crónico/fisiopatología , Dolor Crónico/psicología , Depresión , Femenino , Infecciones por VIH/fisiopatología , Humanos , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/virología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunología
15.
Physiol Behav ; 174: 83-88, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28288793

RESUMEN

Chronic pain affects the lives of millions yearly, but few new treatments are available. Due to decreasing budgets and increasing costs of preclinical research, alternatives are sought with high translatability and low cost. Here we demonstrate the utility of a zebrafish-based model of nociception to serve as a novel screening tool for analgesic drugs. Zebrafish swimming behavior was measured following administration of various algogens including histamine, cinnamaldehyde, mustard oil, acetic acid and complete Freund's adjuvant. All compounds reduce distance traveled, thought to be an expression of nociception. Additionally, the suppression of swimming was attenuated by administration of the common analgesic, morphine. Together these data provide support for the use of zebrafish as a cost-effective and translatable model of nociception.


Asunto(s)
Modelos Animales de Enfermedad , Morfina/farmacología , Morfina/uso terapéutico , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Ácido Acético/toxicidad , Acroleína/análogos & derivados , Acroleína/toxicidad , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Antineoplásicos Fitogénicos/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Adyuvante de Freund/toxicidad , Histamina/toxicidad , Agonistas de los Receptores Histamínicos/toxicidad , Masculino , Planta de la Mostaza/toxicidad , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/inducido químicamente , Aceites Vegetales/toxicidad , Natación , Pez Cebra
16.
J Neurosci Res ; 95(6): 1271-1281, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27452349

RESUMEN

Females greatly outnumber males as sufferers of chronic pain. Although social and psychological factors certainly play a role in the differences in prevalence and incidence, biological differences in the functioning of the immune system likely underlie these observed effects. This Review examines the current literature on biological sex differences in the functioning of the innate and adaptive immune systems as they relate to pain experience. With rodent models, we and others have observed that male mice utilize microglia in the spinal cord to mediate pain, whereas females preferentially use T cells in a similar manner. The difference can be traced to differences in cell populations, differences in suppression by hormones, and disparate cellular responses in males and females. These sex differences also translate into human cellular responses and may be the mechanism by which the disproportionate chronic pain experience is based. Recognition of the evidence underlying sex differences in pain will guide development of treatments and provide better options for patients that are tailored to their physiology. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Dolor , Caracteres Sexuales , Animales , Femenino , Humanos , Masculino
17.
Proc Natl Acad Sci U S A ; 113(42): 11949-11954, 2016 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-27698114

RESUMEN

A response to environmental stress is critical to alleviate cellular injury and maintain cellular homeostasis. Eukaryotic initiation factor 2 (eIF2) is a key integrator of cellular stress responses and an important regulator of mRNA translation. Diverse stress signals lead to the phosphorylation of the α subunit of eIF2 (Ser51), resulting in inhibition of global protein synthesis while promoting expression of proteins that mediate cell adaptation to stress. Here we report that eIF2α is instrumental in the control of noxious heat sensation. Mice with decreased eIF2α phosphorylation (eIF2α+/S51A) exhibit reduced responses to noxious heat. Pharmacological attenuation of eIF2α phosphorylation decreases thermal, but not mechanical, pain sensitivity, whereas increasing eIF2α phosphorylation has the opposite effect on thermal nociception. The impact of eIF2α phosphorylation (p-eIF2α) on thermal thresholds is dependent on the transient receptor potential vanilloid 1. Moreover, we show that induction of eIF2α phosphorylation in primary sensory neurons in a chronic inflammation pain model contributes to thermal hypersensitivity. Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2α, represents a mechanism that could be used to alleviate pathological heat sensation.


Asunto(s)
Factor 2 Eucariótico de Iniciación/metabolismo , Nocicepción , Temperatura , Animales , Conducta Animal , Biomarcadores , Calcio/metabolismo , Células Cultivadas , Factor 2 Eucariótico de Iniciación/genética , Ganglios Espinales/metabolismo , Inmunohistoquímica , Ratones , Ratones Noqueados , Ratones Transgénicos , Imagen Molecular , Neuronas/metabolismo , Dolor/etiología , Dolor/metabolismo , Umbral del Dolor , Fosforilación , Transducción de Señal , Médula Espinal/metabolismo , Estrés Fisiológico , Canales Catiónicos TRPV/metabolismo , eIF-2 Quinasa/metabolismo
19.
J Pain ; 17(1): 119-25, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26597348

RESUMEN

UNLABELLED: Obesity and chronic pain are often comorbid and their rates are increasing. It is unknown whether increased pain is caused by greater weight or poor diet quality or both. Therefore, we utilized a Total Western Diet (TWD) to investigate the functional and physiologic consequences of nutritionally poor diet in mice. For 13 weeks on the commercially available TWD, based on the National Health and Nutrition Examination Survey, thresholds of TWD-fed mice significantly increased in both thermal and mechanical tests. Quantitative magnetic resonance imaging revealed a significant increase in fat mass with a concomitant decrease in lean mass in the TWD-fed mice. In addition, there were significant increases in levels of serum leptin and inflammatory cytokines. After chronic pain induction using complete Freund's adjuvant, hypersensitivity was more pronounced and significantly prolonged in the TWD-fed mice. Therefore, prolonged exposure to poor diet quality resulted in altered acute nociceptive sensitivity, systemic inflammation, and persistent pain after inflammatory pain induction. PERSPECTIVE: These results highlight the negative effects of poor diet quality with respect to recovery from hypersensitivity and susceptibility to chronic pain. A complete understanding of the impact of diet can aid in treatment and recovery dynamics in human clinical patients.


Asunto(s)
Dolor Crónico/fisiopatología , Dieta Occidental , Hiperalgesia/fisiopatología , Inflamación/fisiopatología , Obesidad/fisiopatología , Umbral del Dolor/fisiología , Animales , Dolor Crónico/sangre , Dolor Crónico/complicaciones , Citocinas/sangre , Adyuvante de Freund , Hiperalgesia/sangre , Hiperalgesia/complicaciones , Inflamación/sangre , Inflamación/complicaciones , Leptina/sangre , Masculino , Ratones , Obesidad/sangre , Obesidad/complicaciones
20.
Elife ; 42015 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-26678009

RESUMEN

Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception.


Asunto(s)
Proteínas Portadoras/metabolismo , Regulación de la Expresión Génica , Nocicepción , Fosfoproteínas/metabolismo , Biosíntesis de Proteínas , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas Portadoras/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de Ciclo Celular , Factor 4E Eucariótico de Iniciación/metabolismo , Factores Eucarióticos de Iniciación , Eliminación de Gen , Ratones , Fosfoproteínas/genética
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