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1.
Aust N Z J Public Health ; 43(5): 496-503, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31535432

RESUMEN

OBJECTIVE: To provide insights into complexities of seeking access to state and federal cross-jurisdictional data for linkage with the Australian Childhood Immunisation Register (ACIR). We provide recommendations for improving access and receipt of linked datasets involving Australian Government-administered data. METHODS: We describe requirements for linking eleven federal and state data sources to establish a national linked dataset for safety evaluation of vaccines. The required data linkage methodology for integrating cross-jurisdictional data sources is also described. RESULTS: Extensive negotiation was required with 18 different agencies for 21 separate authorisations and 12 ethics approvals. Three variations of the 'best practice' linkage model were implemented. Australian Government approval requests spanned nearly four years from initial request for data, with a further year before ACIR data transfer to the linkage agency. CONCLUSIONS: Integration of immunisation registers with other data collections is achievable in Australia but infeasible for routine and rapid identification of vaccine safety concerns. Lengthy authorisation requirements, convoluted disparate application processes and inconsistencies in data supplied all contribute to delayed data availability. Implications for public health: Delayed data access for safety surveillance prevents timely epidemiological reviews. Poor responsiveness to safety concerns may erode public confidence, compromising effectiveness of vaccination programs through reduced participation.


Asunto(s)
Control de Enfermedades Transmisibles/estadística & datos numéricos , Recolección de Datos/legislación & jurisprudencia , Inmunización , Registro Médico Coordinado , Sistema de Registros , Vacunación/estadística & datos numéricos , Australia , Niño , Humanos , Programas de Inmunización , Formulación de Políticas , Vacunas
2.
J Physiol ; 597(13): 3425-3439, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31077379

RESUMEN

KEY POINTS: While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain. ABSTRACT: It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABAA or GABAB receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABAA and GABAB receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABAA and GABAB receptor agonists, the VMR was only consistently increased by GABAA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain.

4.
J Pain ; 20(7): 810-818, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30659887

RESUMEN

Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice with respect to both the properties and distribution of nAChR currents in sensory neurons. Because both species are used to understand pain signaling in humans, we sought to determine whether the currents present in either species was reflective of those present in human sensory neurons. Neurons from the L4/L5 dorsal root ganglia were obtained from adult male and female organ donors. Nicotine evoked currents were detected in 40 of 47 neurons (85%). In contrast with the naïve mouse, in which almost all nAChR currents are transient, or the rat, in which both mouse-like transient and more slowly activating and inactivating currents are detected, all the currents in human DRG neurons were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists mecamylamine (30 µmol/L), but not by the TRPA1 selective antagonist HC-030031 (10 µmol/L). Single cell polymerase chain reaction analysis of nicotinic receptor subunit expression in human DRG neurons are consistent with functional data indicating that receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors). The most prevalent coexpression pattern was α3/ß2 (95 ± 4% of neurons with subunits), but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that there are not only species differences in the sensory neuron distribution of nAChR currents between rodent and human, but that the subunit composition of the channel underlying human nAChR currents may be different from those in the mouse or rat. PERSPECTIVE: The properties and distribution of nicotine evoked currents in human sensory neurons were markedly different from those previously observed in mice and rats. These observations add additional support to the suggestion that human sensory neurons may be an essential screening tool for those considering moving novel therapeutics targeting primary afferents into clinical trials.

5.
Vaccine ; 37(2): 280-288, 2019 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-30503081

RESUMEN

OBJECTIVE: To determine whether differences in combination DTaP vaccine types at 2, 4 and 6 months of age were associated with mortality (all-cause or non-specific), within 30 days of vaccination. DESIGN: Observational nationwide cohort study. SETTING: Linked population data from the Australian Childhood Immunisation Register and National Death Index. PARTICIPANTS: Australian infants administered a combination trivalent, quadrivalent or hexavalent DTaP vaccine (DTaP types) between January 1999 and December 2010 at 2, 4 and 6 months as part of the primary vaccination series. The study population included 2.9, 2.6, & 2.3 million children in the 2, 4 and 6 month vaccine cohorts, respectively. MAIN OUTCOME MEASURES: Infants were evaluated for the primary outcome of all-cause mortality within 30 days. A secondary outcome was non-specific mortality (unknown cause of death) within 30 days of vaccination. Non-specific mortality was defined as underlying or other cause of death codes, R95 'Sudden infant death syndrome', R96 'Other sudden death, cause unknown', R98 'Unattended death', R99 'Other ill-defined and unspecified cause of mortality' or where no cause of death was recorded. RESULTS: The rate of 30 day all-cause mortality was low and declined from 127.4 to 59.3 deaths per 100,000 person-years between 2 and 6 month cohorts. When compared with trivalent DTaP vaccines, no elevated risk in all-cause or non-specific mortality was seen with any quadrivalent or hexavalent DTaP vaccines, for any cohort. CONCLUSION: Use of routine DTaP combination vaccines with differing disease antigens administered during the first six months of life is not associated with infant mortality.


Asunto(s)
Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/administración & dosificación , Mortalidad Infantil , Vacunación/estadística & datos numéricos , Tos Ferina/prevención & control , Australia/epidemiología , Estudios de Cohortes , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/efectos adversos , Femenino , Humanos , Lactante , Masculino , Registro Médico Coordinado , Sistema de Registros , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/efectos adversos , Tos Ferina/epidemiología
6.
Neurosurgery ; 84(1): 60-65, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29425330

RESUMEN

BACKGROUND: While high-resolution imaging is increasingly used in guiding decisions about surgical interventions for the treatment of trigeminal neuralgia, direct assessment of the extent of vascular contact of the trigeminal nerve is still considered the gold standard for the determination of whether nerve decompression is warranted. OBJECTIVE: To compare intraoperative and magnetic resonance imaging (MRI) findings of the prevalence and severity of vascular compression of the trigeminal nerve in patients without classical trigeminal neuralgia. METHODS: We prospectively recruited 27 patients without facial pain who were undergoing microvascular decompression for hemifacial spasm and had undergone high-resolution preoperative MRI. Neurovascular contact/compression (NVC/C) by artery or vein was assessed both intraoperatively and by MRI, and was stratified into 3 types: simple contact, compression (indentation of the surface of the nerve), and deformity (deviation or distortion of the nerve). RESULTS: Intraoperative evidence of NVC/C was detected in 23 patients. MRI evidence of NVC/C was detected in 18 patients, all of whom had intraoperative evidence of NVC/C. Thus, there were 5, or 28% more patients in whom NVC/C was detected intraoperatively than with MRI (Kappa = 0.52); contact was observed in 4 of these patients and compression in 1 patient. In patients where NVC/C was observed by both methods, there was agreement regarding the severity of contact/compression in 83% (15/18) of patients (Kappa = 0.47). No patients exhibited deformity of the nerve by imaging or intraoperatively. CONCLUSION: There was moderate agreement between imaging and operative findings with respect to both the presence and severity of NVC/C.


Asunto(s)
Cirugía para Descompresión Microvascular , Síndromes de Compresión Nerviosa/diagnóstico por imagen , Síndromes de Compresión Nerviosa/cirugía , Procedimientos Neuroquirúrgicos/métodos , Enfermedades del Nervio Trigémino/diagnóstico por imagen , Enfermedades del Nervio Trigémino/cirugía , Adulto , Anciano , Nervio Facial/cirugía , Femenino , Espasmo Hemifacial/diagnóstico por imagen , Espasmo Hemifacial/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Síndromes de Compresión Nerviosa/epidemiología , Prevalencia , Estudios Prospectivos , Nervio Trigémino/anomalías , Nervio Trigémino/diagnóstico por imagen , Enfermedades del Nervio Trigémino/epidemiología , Neuralgia del Trigémino/epidemiología , Adulto Joven
7.
Artículo en Inglés | MEDLINE | ID: mdl-31891824

RESUMEN

BACKGROUND: Rates of food allergy have increased markedly in Australia and other high- income countries in recent years. On the basis of ecological observations, and the known immunologic characteristics of whole-cell pertussis (wP) compared with acellular pertussis (aP) vaccines, we hypothesized that wP vaccination in infancy protects against the development of food allergy. OBJECTIVE: To determine whether infants who receive wP in infancy were less likely to develop IgE-mediated food allergy than those who received aP. METHODS: Retrospective cohort-nested case-control study of Australian children born in the period 1997 to 1999, the period of transition from using wP-containing to aP-containing vaccines. Children diagnosed with IgE-mediated food allergy were individually matched to 10 controls by date of birth, socioeconomic decile, and jurisdiction of birth. The odds ratio of vaccination with wP versus aP among cases and matched controls was calculated using conditional logistic regression. RESULTS: The odds ratio of receiving the first dose as wP (rather than aP) among cases of food allergy compared with controls was 0.77 (95% CI, 0.62-0.95). The results of secondary analyses (any dose as wP vs aP-only, and wP-only vs aP-only) were broadly similar. CONCLUSIONS: Australian infants who received wP vaccines were less likely to be diagnosed with food allergy in childhood than contemporaneous children who received aP vaccines. If a protective effect is confirmed in a randomized controlled trial, wP or mixed wP and aP vaccination schedules could form part of an effective strategy for combating the rise in food allergies.

8.
BMJ Open ; 8(10): e023263, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30341132

RESUMEN

OBJECTIVE: To actively solicit adverse events experienced in the days following immunisation with quadrivalent inactivated influenza vaccine using Australia's near real-time, participant-based vaccine safety surveillance system, AusVaxSafety. DESIGN AND SETTING: Observational cohort study conducted in 194 sentinel surveillance immunisation sites (primary care, hospital and community-based clinics) across Australia. PARTICIPANTS: Individuals aged ≥6 months who received a routine seasonal influenza vaccine at a participating site (n=102 911) and responded to a survey (via short message service or email) sent 3 days after vaccination about adverse events experienced (n=73 892; 71.8%). MAIN OUTCOME MEASURE: Near real-time and cumulative participant-reported rates of any adverse event, fever or medical attendance experienced within 3 days after vaccination overall, by brand, age, pregnancy status and concomitant vaccine receipt. RESULTS: Participant median age was 57 years (range: 6 months to 102 years); 58.1% (n=42 869) were female and 2.7% (n=2018) were pregnant. Near real-time fast initial response cumulative summation and Bayesian analyses of weekly event rates did not demonstrate a safety signal. Children aged 6 months to 4 years had higher event rates (522/6180; 8.4%) compared with older ages; participants aged ≥65 years reported fewer events (1695/28 154; 6.0%). There were no clinically significant differences in safety between brands, by age group or overall. Cumulative data analysis demonstrated that concomitant vaccination was associated with increased rates of fever (2.1% vs 0.8%) and medical attendance (0.8% vs 0.4%), although all rates were low and did not exceed expected levels. CONCLUSIONS: Novel, postmarketing AusVaxSafety surveillance demonstrated comparable and expected safety outcomes for the 2017 quadrivalent inactivated influenza vaccine brands used in Australia. These near real-time, participant-reported data are expected to encourage confidence in vaccine safety and promote uptake.


Asunto(s)
Vacunas contra la Influenza/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Factores de Edad , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Niño , Preescolar , Femenino , Humanos , Lactante , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/prevención & control , Masculino , Persona de Mediana Edad , Estaciones del Año , Vigilancia de Guardia , Adulto Joven
9.
Neuron ; 99(6): 1274-1288.e6, 2018 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-30236284

RESUMEN

Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.


Asunto(s)
Neuronas Aferentes/efectos de los fármacos , Dolor/tratamiento farmacológico , Receptores Opioides kappa/antagonistas & inhibidores , Transducción de Señal/fisiología , Animales , Axones/fisiología , Ratones , Ratones Transgénicos , Neuronas/fisiología , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Manejo del Dolor , Receptores Opioides kappa/metabolismo
10.
Pain ; 159 Suppl 1: S1-S2, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30113940
11.
Pain ; 159(8): 1484-1493, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29578943

RESUMEN

Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is believed to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.


Asunto(s)
Interneuronas/fisiología , Neuronas/fisiología , Dolor/fisiopatología , Asta Dorsal de la Médula Espinal/fisiopatología , Médula Espinal/fisiopatología , Animales , Ratones , Técnicas de Placa-Clamp
12.
BMJ Open ; 8(1): e020232, 2018 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-29391374

RESUMEN

INTRODUCTION: Atopic diseases, including food allergy, have become a predominant cause of chronic illness among children in developed countries. In Australia, a rise in hospitalisations among infants coded as anaphylaxis to foods coincided with the replacement of whole-cell pertussis (wP) vaccine with subunit acellular pertussis (aP) vaccine on the national immunisation schedule in the late 1990s. Atopy is characterised by a tendency to mount T helper type 2 (Th2) responses to otherwise innocuous environmental antigens. Compared with infants who receive aP as their first pertussis vaccine, those who receive wP appear less likely to mount Th2 immune responses to either vaccine or extraneous antigens. We therefore speculate that removal of wP from the vaccine schedule contributed to the observed rise in IgE-mediated food allergy among Australian infants. METHODS AND ANALYSIS: This is a retrospective individually matched case-control study among a cohort of Australian children born from 1997 to 1999, the period of transition from wP to aP vaccines; we include in the cohort children listed on Australia's comprehensive population-based immunisation register as having received a first dose of either pertussis vaccine by 16 weeks old. 500 cohort children diagnosed as having IgE-mediated food allergy at specialist allergy clinics will be included as cases. Controls matched to each case by date and jurisdiction of birth and regional socioeconomic index will be sampled from the immunisation register. Conditional logistic regression will be used to estimate OR (±95% CI) of receipt of wP (vs aP) as the first vaccine dose among cases compared with controls. ETHICS AND DISSEMINATION: The study is approved by all relevant human research ethics committees: Western Australia Child and Adolescent Health Services (2015052EP), Women's and Children's Hospital (HREC/15/WCHN/162), Royal Children's Hospital (35230A) and Sydney Children's Hospital Network (HREC/15/SCHN/405). Outcomes will be disseminated through publication and scientific presentation. TRIAL REGISTRATION NUMBER: NCT02490007.


Asunto(s)
Hipersensibilidad a los Alimentos/etiología , Esquemas de Inmunización , Vacuna contra la Tos Ferina/efectos adversos , Vacunación , Tos Ferina/prevención & control , Adolescente , Anticuerpos Antibacterianos/sangre , Antígenos , Estudios de Casos y Controles , Protocolos Clínicos , Vacuna contra Difteria, Tétanos y Tos Ferina , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular , Femenino , Hipersensibilidad a los Alimentos/sangre , Humanos , Inmunoglobulina E/sangre , Lactante , Masculino , Vacuna contra la Tos Ferina/clasificación , Proyectos de Investigación , Estudios Retrospectivos , Factores de Riesgo , Australia Occidental
13.
Pain Med ; 19(8): 1525-1549, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29077871

RESUMEN

Objective: Persistent pain causes untold misery worldwide and is a leading cause of disability. Despite its astonishing prevalence, pain is undertreated, at least in part because existing therapeutics are ineffective or cause intolerable side effects. In this review, we cover new findings about the neurobiology of pain and argue that all but the most transient forms of pain needed to avoid tissue damage should be approached as a disease where a cure can be the goal of all treatment plans, even if attaining this goal is not yet always possible. Design: We reviewed the literature to highlight recent advances in the area of the neurobiology of pain. Results: We discuss barriers that are currently hindering the achievement of this goal, as well as the development of new therapeutic strategies. We also discuss innovations in the field that are creating new opportunities to treat and even reverse persistent pain, some of which are in late-phase clinical trials. Conclusion: We conclude that the confluence of new basic science discoveries and development of new technologies are creating a path toward pain therapeutics that should offer significant hope of a cure for patients and practitioners alike. Classification of Evidence. Our review points to new areas of inquiry for the pain field to advance the goal of developing new therapeutics to treat chronic pain.


Asunto(s)
Sensibilización del Sistema Nervioso Central/fisiología , Dolor Crónico/fisiopatología , Humanos
14.
Anesth Analg ; 126(5): 1598-1605, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29239949

RESUMEN

BACKGROUND: Using labor, epidural analgesia has been linked to a reduced risk of postpartum depression, but the role of labor pain relief in this association remains unclear. The goal of this study was to test the hypothesis that effective epidural analgesia during labor is associated with reduced postpartum depression symptomatology. METHODS: A single, institutional, retrospective, observational cohort design was chosen. The primary outcome was Edinburgh postnatal depression scale (EPDS) score, measured at the 6-week postpartum visit. Subjects included in the final analysis had (1) received labor epidural analgesia; (2) pain assessed during labor both before and during initiation of labor epidural analgesia by 0-10 numeric rating scores; and (3) depression risk assessed by the EPDS and documented at their 6-week postpartum visit. Simple and multiple linear regression was used to identify the best model for assessing the association between pain improvement, defined as percent improvement in pain (PIP), and depression, after adjusting for a history of anxiety or depression, other psychiatric history, abuse, trauma, mode of delivery, and other maternal or fetal comorbid diseases. RESULTS: Two hundred one patients were included in the final analysis. Women with higher improvements in pain were associated with lower EPDS scores (r = 0.025; P = .002). Variables known to be associated with depression (body mass index, anxiety and/or depression, third- and fourth-degree perineal lacerations, and anemia) were significantly correlated with EPDS score and included in the final model. After we adjusted for these covariates, PIP remained a significant predictor of EPDS score (r = 0.49; P = .008), accounting for 6.6% of the variability in postpartum depression scores. The full model including pain, body mass index, anxiety and/or depression, perineal lacerations, and anemia explained 24% of the variability in postpartum depression scores. CONCLUSIONS: Although the extent of labor pain relief by epidural analgesia predicts lower postpartum depression scores, the relative contribution of PIP to risk for postpartum depression symptoms may be less than other established risk factors for depression. These data support that the clinical significance of labor analgesia in the development of postpartum depression needs to be more clearly defined.


Asunto(s)
Analgesia Epidural/psicología , Depresión Posparto/diagnóstico , Depresión Posparto/psicología , Dolor de Parto/psicología , Manejo del Dolor/psicología , Adulto , Analgesia Epidural/tendencias , Estudios de Cohortes , Depresión Posparto/epidemiología , Femenino , Humanos , Dolor de Parto/tratamiento farmacológico , Dolor de Parto/epidemiología , Manejo del Dolor/tendencias , Valor Predictivo de las Pruebas , Embarazo , Estudios Retrospectivos
15.
Elife ; 62017 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-28508747

RESUMEN

Available evidence indicates voltage-gated Na+ channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na+ currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms.


Asunto(s)
Cationes/metabolismo , Ganglios Espinales/metabolismo , Neuronas/metabolismo , Sodio/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Humanos , Técnicas de Placa-Clamp , Ratas
17.
J Neurosci ; 37(14): 3741-3752, 2017 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-28264976

RESUMEN

The δ opioid receptor (δR) is a promising alternate target for pain management because δR agonists show decreased abuse potential compared with current opioid analgesics that target the µ opioid receptor. A critical limitation in developing δR as an analgesic target, however, is that δR agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of δR in sensory neurons contributes to this low δR agonist efficacy in vivo by limiting surface δR expression. Using direct visualization of δR trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains δR in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases δR from this checkpoint and stimulates delivery of exogenous and endogenous δR to the neuronal surface both in vitro and in vivo PTEN inhibition in vivo increases the percentage of TG neurons expressing δR on the surface and allows efficient δR-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the δR, explain the low efficacy of δR agonists in vivo, and provide evidence that active δR relocation is a viable strategy to increase δR antinociception.SIGNIFICANCE STATEMENT Opioid analgesics, such as morphine, which target the µ opioid receptor (µR), have been the mainstay of pain management, but their use is highly limited by adverse effects and their variable efficacy in chronic pain. Identifying alternate analgesic targets is therefore of great significance. Although the δ opioid receptor (δR) is an attractive option, a critical limiting factor in developing δR as a target has been the low efficacy of δR agonists. Why δR agonists show low efficacy is still under debate. This study provides mechanistic and functional data that intracellular localization of δR in neurons is a key factor that contributes to low agonist efficacy, and presents a proof of mechanism that relocating δR improves efficacy.


Asunto(s)
Membrana Celular/metabolismo , Neuronas/metabolismo , Fosfohidrolasa PTEN/fisiología , Receptores Opioides delta/metabolismo , Animales , Membrana Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Células PC12 , Fosfohidrolasa PTEN/antagonistas & inhibidores , Fenantrenos/farmacología , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiología , Ratas , Ratas Sprague-Dawley
18.
Cell Calcium ; 62: 16-28, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28109678

RESUMEN

We have recently demonstrated that in a rat model of chemotherapy-induced peripheral neuropathy (CIPN), there is a significant decrease in the duration of the depolarization-evoked Ca2+ transient in small diameter, IB4+, and capsaicin-responsive neurons innervating the glabrous skin of the hindpaw. This change was specific to the transient duration and significantly smaller if not undetectable in neurons innervating the dorsal skin of the hindpaw or the skin of the inner thigh. Given the importance of mitochondria in intracellular Ca2+ regulation and the findings of chemotherapy-associated increase in mitotoxicity along the sensory neuron axons, we hypothesized that CIPN is due to both increases and decreases in mitochondria function, with changes manifest in distinct subpopulations of afferents. To begin to test this hypothesis, we used confocal microscopy and Ca2+ imaging in combination with pharmacological manipulations to study paclitaxel-induced changes in retrograde tracer-labeled neurons from naïve, vehicle-treated, and paclitaxel-treated rats. Paclitaxel treatment was not associated with decreased mitochondrial membrane potential or increased superoxide levels in the somata of putative nociceptive glabrous skin neurons. However, it was associated with significant increases in the relative contribution of mitochondria to the control of the evoked Ca2+ transient duration in putative nociceptive glabrous skin neurons, as well as increases in mitotracker and Tom20 staining which reflected an increase in mitochondrial volume. Furthermore, the relative contribution of the sarco-endoplasmic reticulum Ca2+ ATPase to the regulation of the duration of the depolarization evoked Ca2+ transient was also increased in this subpopulation of neurons from paclitaxel treated rats. Our results indicate that the paclitaxel-induced decrease in the duration of the evoked Ca2+ transient is due to both direct and indirect influences of mitochondria. It remains to be determined if and how these changes contribute to the manifestation of CIPN.


Asunto(s)
Calcio/metabolismo , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Nociceptores/efectos de los fármacos , Paclitaxel/farmacología , Piel/efectos de los fármacos , Animales , Masculino , Mitocondrias/metabolismo , Neuronas/citología , Neuronas/metabolismo , Nociceptores/metabolismo , Ratas , Ratas Sprague-Dawley , Piel/metabolismo
19.
Cephalalgia ; 37(1): 36-48, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26970607

RESUMEN

Aim of investigation Due to compelling evidence in support of links between sex, stress, sympathetic post-ganglionic innervation, dural immune cells, and migraine, our aim was to characterize the impacts of these factors on the type and proportion of immune cells in the dura. Methods Dural immune cells were obtained from naïve or stressed adult male and female Sprague Dawley rats for flow cytometry. Rats with surgical denervation of sympathetic post-ganglionic neurons of the dura were also studied. Results Immune cells comprise ∼17% of all cells in the dura. These included: macrophages/granulocytes ("Macs"; 63.2% of immune cells), dendritic cells (0.88%), T-cells (4.51%), natural killer T-cells (0.51%), natural killer cells (3.08%), and B-cells (20.0%). There were significantly more Macs and fewer B- and natural killer T-cells in the dura of females compared with males. Macs and dendritic cells were significantly increased by stress in males, but not females. In contrast, T-cells were significantly increased in females with a 24-hour delay following stress. Lastly, Macs, dendritic cells, and T-cells were significantly higher in sympathectomized-naïve males, but not females. Conclusions It may not only be possible, but necessary to use different strategies for the most effective treatment of migraine in men and women.


Asunto(s)
Duramadre/inmunología , Trastornos Migrañosos/inmunología , Caracteres Sexuales , Estrés Psicológico , Fibras Adrenérgicas , Animales , Linfocitos B/citología , Recuento de Células , Células Dendríticas/citología , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Inmunohistoquímica , Macrófagos/citología , Masculino , Ratas , Ratas Sprague-Dawley , Simpatectomía , Subgrupos de Linfocitos T/citología
20.
J Allergy Clin Immunol ; 139(5): 1600-1607.e2, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27554812

RESUMEN

BACKGROUND: The ideal age to introduce egg into the infant diet has been debated for the past 2 decades in the context of rising rates of egg allergy. OBJECTIVE: We sought to determine whether regular consumption of egg protein from age 4 to 6 months reduces the risk of IgE-mediated egg allergy in infants with hereditary risk, but without eczema. METHODS: Infants aged 4 to 6 months were randomly allocated to receive daily pasteurized raw whole egg powder (n = 407) or a color-matched rice powder (n = 413) to age 10 months. All infants followed an egg-free diet and cooked egg was introduced to both groups at age 10 months. The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months. RESULTS: There was no difference between groups in the percentage of infants with IgE-mediated egg allergy (egg 7.0% vs control 10.3%; adjusted relative risk, 0.75; 95% CI, 0.48-1.17; P = .20). A higher proportion of participants in the egg group stopped taking the study powder because of a confirmed allergic reaction (25 of 407 [6.1%] compared with 6 of 413 [1.5%]). Egg-specific IgG4 levels were substantially higher in the egg group at 12 months (median, 1.22 mgA/L vs control 0.07 mgA/L; P < .0001). CONCLUSIONS: We found no evidence that regular egg intake from age 4 to 6 months substantially alters the risk of egg allergy by age 1 year in infants who are at hereditary risk of allergic disease and had no eczema symptoms at study entry.


Asunto(s)
Hipersensibilidad al Huevo/prevención & control , Proteínas del Huevo/administración & dosificación , Método Doble Ciego , Hipersensibilidad al Huevo/sangre , Hipersensibilidad al Huevo/diagnóstico , Hipersensibilidad al Huevo/inmunología , Proteínas del Huevo/efectos adversos , Proteínas del Huevo/inmunología , Huevos/efectos adversos , Femenino , Humanos , Inmunoglobulina E/sangre , Lactante , Masculino , Factores de Riesgo
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