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1.
J Chem Phys ; 153(24): 244303, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33380099

RESUMO

This paper presents a joint experimental and theoretical study of positron scattering from furan. Experimental data were measured using the low energy positron beamline located at the Australian National University and cover an energy range from 1 eV to 30 eV. Cross sections were measured for total scattering, total elastic and inelastic scattering, positronium formation, and differential elastic scattering. Two theoretical approaches are presented: the Schwinger multichannel method and the independent atom method with screening corrected additivity rule. In addition, our data are compared to corresponding electron scattering results from the same target with a number of significant differences observed and discussed.

2.
Rev Sci Instrum ; 91(3): 033311, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32259967

RESUMO

We describe the operation of a pulsed positronium beam based on a two-stage buffer gas positron trap (BGT) or a Surko trap. The BGT allows the areal density and temporal spread of the positron beam to be tailored. This tailored positron beam is used to form a positronium beam via charge exchange with an atomic or molecular gas. The resulting positronium beam is energy tunable, and the collimated beam relies on the angular differential positronium production cross section of the atomic or molecular gas used.

3.
J Chem Phys ; 148(14): 144308, 2018 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-29655347

RESUMO

We present a range of cross section measurements for the low-energy scattering of positrons from pyridine, for incident positron energies of less than 20 eV, as well as the independent atom model with the screening corrected additivity rule including interference effects calculation, of positron scattering from pyridine, with dipole rotational excitations accounted for using the Born approximation. Comparisons are made between the experimental measurements and theoretical calculations. For the positronium formation cross section, we also compare with results from a recent empirical model. In general, quite good agreement is seen between the calculations and measurements although some discrepancies remain which may require further investigation. It is hoped that the present study will stimulate development of ab initio level theoretical methods to be applied to this important scattering system.

4.
Phys Rev Lett ; 120(11): 113401, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29601739

RESUMO

The direct single-ionization cross section for Ar by positron impact has been measured in the region above the first ionization threshold. These measurements are compared to semiclassical calculations which give rise to a power law variation of the cross section in the threshold region. The experimental results appear to be in disagreement with extensions to the Wannier theory applied to positron impact ionization, with a smaller exponent than that calculated by most previous works. In fact, in this work, we see no difference in threshold behavior between the positron and electron cases. Possible reasons for this discrepancy are discussed.

6.
J Chem Phys ; 141(3): 034306, 2014 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-25053319

RESUMO

Measurements of the grand total and total positronium formation cross sections for positron scattering from uracil have been performed for energies between 1 and 180 eV, using a trap-based beam apparatus. Angular, quasi-elastic differential cross section measurements at 1, 3, 5, 10, and 20 eV are also presented and discussed. These measurements are compared to existing experimental results and theoretical calculations, including our own calculations using a variant of the independent atom approach.


Assuntos
Elétrons , Uracila/química , Elasticidade , Modelos Moleculares , Teoria Quântica
7.
Nanotechnology ; 25(26): 265402, 2014 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-24919450

RESUMO

We present a transmission electron microscopy (TEM)-compatible, hybrid nanomachined, on-chip construct for probing the structural and electrical changes in individual nanowire electrodes during lithium insertion. We have assembled arrays of individual ß-phase manganese dioxide (ß-MnO2) nanowires (NWs), which are employed as a model material system, into functional electrochemical cells through a combination of bottom-up (dielectrophoresis) and top-down (silicon nanomachining) unit processes. The on-chip NWs are electrochemically lithiated inside a helium-filled glovebox and their electrical conductivity is studied as a function of incremental lithium loading during initial lithiation. We observe a dramatic reduction in NW conductivity (on the order of two to three orders in magnitude), which is not reversed when the lithium is extracted from the nanoelectrode. This conductivity change is attributed to an increase in lattice disorder within the material, which is observed from TEM images of the lithiated NWs. Furthermore, electron energy loss spectroscopy (EELS) was employed to confirm the reduction in valence state of manganese, which occurs due to the transformation of MnO2 to LixMnO2.

8.
Appl Radiat Isot ; 83 Pt B: 77-85, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23395226

RESUMO

We present a study of electron and positron transport in water in both the gaseous and liquid states using a Boltzmann equation analysis and a Monte-Carlo simulation technique. We assess the importance of coherent scattering processes when considering transport of electrons/positrons in dense gases and liquids. We highlight the importance of electron and positron swarm studies and experiments as a test of the accuracy and completeness of cross-sections, as well as a technique for benchmarking Monte-Carlo simulations. The thermalization of low-energy positrons (<150 eV) in water is discussed and the sensitivity of the profiles to the form of the cross-sections in this energy region, and assumptions in the microscopic processes, is considered.


Assuntos
Elétrons , Gases/química , Modelos Teóricos , Método de Monte Carlo
9.
J Chem Phys ; 139(1): 014308, 2013 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-23822304

RESUMO

We present results of measurements and calculations of elastic electron scattering from 1,4-dioxane in the energy range of 0-1000 eV. Absolute differential and integral elastic cross sections have been measured using a crossed electron-molecule beam spectrometer and the relative flow technique, at four energies in the 10-30 eV range and for scattered electrons in the angular range 20°-129°. The measured cross sections are compared with results from R-matrix computations, at the static exchange plus polarization level, calculated at energies between 0-20 eV, and with calculations employing the independent atom model with the screening corrected additivity rule (IAM-SCAR). Those latter computations were conducted at energies between 1 and 1000 eV. Agreement between the measured and R-matrix cross sections was typically found to be good at all common energies, whereas agreement with IAM-SCAR was satisfactory only at 30 eV. To the best of our knowledge, the present results are the first absolute data to be published in the literature for this scattering system.


Assuntos
Dioxanos/química , Elétrons , Modelos Moleculares , Modelos Teóricos
10.
J Chem Phys ; 138(21): 214305, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23758369

RESUMO

Differential, integral, and momentum transfer cross sections have been determined for the elastic scattering of electrons from the molecules CF3Cl, CF2Cl2, and CFCl3.With the help of a crossed electron beam-molecular beam apparatus using the relative flow technique, the ratios of the elastic differential cross sections (DCSs) of CF3Cl, CF2Cl2, and CFCl3 to those of He were measured in the energy region from 1.5 to 100 eV and at scattering angles in the range 15° to 130°. From those ratios, the absolute DCSs were determined by utilizing the known DCS of He. For CF3Cl and CF2Cl2, at the common energies of measurement, we find generally good agreement with the results from the independent experiments of Mann and Linder [J. Phys. B 25, 1621 (1992); and ibid. 25, 1633 (1992)]. In addition, as a result of progressively substituting a Cl-atom, undulations in the angular distributions have been found to vary in a largely systematic manner in going from CF4 to CF3Cl to CF2Cl2 to CFCl3 and to CCl4. These observed features suggest that the elastic scattering process is, in an independently additive manner, dominated by the atomic-Cl atoms of the molecules. The present independent atom method calculation typically supports the experimental evidence, within the screened additivity rule formulation, for each species and for energies greater than about 10-20 eV. Integral elastic and momentum transfer cross sections were also derived from the measured DCSs, and are compared to the other available theoretical and experimental results. The elastic integral cross sections are also evaluated as a part of their contribution to the total cross section.

11.
J Chem Phys ; 137(20): 204307, 2012 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-23206003

RESUMO

We report on new measurements for elastic electron scattering from pyrazine. Absolute differential cross sections (DCSs) at seven discrete energies in the range 3-50 eV, and over the scattered electron angular range 10°-129°, were determined using a crossed electron-molecular beam spectrometer in conjunction with the well-established relative flow technique. Integral elastic cross sections were subsequently derived from those DCS data at each energy. Where possible comparison between the present results and those from sophisticated Schwinger multichannel and R-matrix computations is made, with generally quite good quantitative accord being found. Finally, in order to better study some of the rich resonance structure predicted by theory, results from elastic electron excitation functions are presented.

12.
Nanotechnology ; 22(27): 275308, 2011 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-21602618

RESUMO

Measurements of the electrical and thermal transport properties of one-dimensional nanostructures (e.g. nanotubes and nanowires) are typically obtained without detailed knowledge of the specimen's atomic-scale structure or defects. To address this deficiency, we have developed a microfabricated, chip-based characterization platform that enables both transmission electron microscopy (TEM) of the atomic structure and defects as well as measurement of the thermal transport properties of individual nanostructures. The platform features a suspended heater line that physically contacts the center of a suspended nanostructure/nanowire that was placed using in situ scanning electron microscope nanomanipulators. Suspension of the nanostructure across a through-hole enables TEM characterization of the atomic and defect structure (dislocations, stacking faults, etc) of the test sample. This paper explains, in detail, the processing steps involved in creating this thermal property measurement platform. As a model study, we report the use of this platform to measure the thermal conductivity and defect structure of a GaN nanowire.

13.
Plant Dis ; 95(5): 612, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-30731965

RESUMO

Eastern hemlock (Tsuga canadensis) is an ecologically and economically important conifer from the north-central United States to the east coast of North America to the southern Appalachian Mountains. In early spring 2010, blighted shoot tips of eastern hemlock were observed at widely separated locations in the Chattahoochee National Forest in north Georgia. Damage did not appear to be directly related to hemlock woolly adelgid (Adelges tsugae) activity, which was sporadic or absent in some areas where symptoms were observed. A preliminary survey in March 2010 revealed that incidence of blighted shoots on individual trees varied, but was as high as 70%. Stems of shoots produced the previous year were frequently necrotic, had lost needles, and bore pycnidia with hyaline, two-celled conidia consistent with those of Sirococcus tsugae (2,3). Later in the spring and summer, shoots of the current year's growth became blighted, with sporulation of S. tsugae also on dead and dying needles. While S. tsugae previously has been reported on T. heterophylla, T. mertensiana, Cedrus atlantica, and C. deodara in western North America, it has only recently been reported on eastern hemlock (1), and its ability to induce shoot blight has not been proven. Pure cultures (2,3) were obtained on streptomycin-amended potato dextrose agar (PDA) and their identity was confirmed by species-specific PCR primers (4). Nuclear rDNA internal transcribed spacer sequence (554 nucleotides) also was obtained for isolate 10-05 and deposited in GenBank (Accession No. HQ256769). This sequence was found to be identical to sequences previously deposited for S. tsugae isolates. Isolate 10-05 and a second isolate (10-06) were used to inoculate potted 2-year-old eastern hemlock seedlings in a growth chamber at 20°C with a 16-h photoperiod. Conidia were collected by flooding 1-month-old colonies on PDA with sterile water. Expanding shoots on one branch of each seedling were wounded using scissors to cut the tips off needles and stems, while another branch remained nonwounded. Ten seedlings per isolate were inoculated by spraying to runoff with a suspension of 5 × 106 conidia ml-1 in sterile water, and five similarly treated control seedlings were sprayed with sterile water. Seedlings were covered with plastic bags to maintain high humidity for 4 days. Germination of conidia of each isolate incubated on water agar in this growth chamber was >80% after 24 h. Symptoms were evaluated and reisolation was attempted on streptomycin-amended PDA 2 months after inoculation. Symptoms of seedlings inoculated with either isolate included chlorotic and necrotic needle spots, browning of cut edges of needles, browning and death of needle tips and entire needles, death of stem tips with retention of dead needles, and needle loss. Symptoms of control seedlings were limited to slight browning of cut edges of needles. The fungus was reisolated from wounded shoots of 17 of 20 inoculated seedlings and nonwounded shoots of 5 of 20 inoculated seedlings and was not cultured from control seedlings. To our knowledge, this is the first report of S. tsugae in Georgia and also the first demonstration of its ability to produce symptoms that have been attributed to it on any tree species. References: (1) M. Miller-Weeks and W. Ostrofsky. USDA. Forest Service. Online publication. NA-PR-01-10, 2010. (2) A. Y. Rossman et al. For. Pathol. 38:47. (3) D. R. Smith et al. For. Pathol. 33:141, 2003. (4) D. R. Smith and G. R. Stanosz. For. Pathol. 38:156, 2008.

14.
Phys Rev Lett ; 105(7): 073201, 2010 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-20868040

RESUMO

Channel coupling is a phenomenon that has been investigated for many scattering processes, and is responsible for the formation of cusps or steps in the cross sections for open scattering channels at, or near, the onset of a new scattering channel. It has long been speculated that the opening of the positronium formation channel may lead to the formation of such cusp features in the elastic positron scattering cross section. In this work, elastic scattering of positrons has been measured in the region of the positronium formation threshold for the noble gases He-Xe. Cusplike behavior is observed and, while the features which are observed appear broad, they represent a magnitude of between 4 and 15% of the total elastic cross section. No evidence is found of any other features in this region, at least within the uncertainty of the present data, discounting the possibility of scattering resonances.

15.
J Pharmacol Exp Ther ; 335(2): 506-15, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20724485

RESUMO

Dopamine receptors play a critical role in reward-related learning, but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol [4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one] with the D3 receptor-preferring antagonist 2,3-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4] triazol-3-yisulfanyl)-propyl]-piperazin-1-y1}-pyrimidine hydrochloride (ABT-127), given at D3 receptor-selective doses [i.e., no displacement of [(3)H]3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide binding, no effects on γ-butyrolactone-induced striatal l-3,4-dihydroxyphenylalanine; haloperidol accumulation; no attenuation of apomorphine-induced stereotypy]. We hypothesized that haloperidol and ABT-127 will produce a doubly dissociable effect on acquisition versus expression of cocaine-conditioned activity. Rats received three 1-h habituation sessions to activity monitors followed by three 1-h cocaine (10 mg/kg) conditioning sessions. The expression phase (no cocaine injections) took place 48 h later. Haloperidol (50 µ/kg) given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT-127 (1.0 mg/kg), when given during conditioning, failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are more critically involved in acquisition than initial expression and D3 receptors are more critically involved in expression than acquisition of conditioned activity based on cocaine.


Assuntos
Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Animais , Ligação Competitiva , Linhagem Celular , Clonagem Molecular , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Agonistas de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Haloperidol/metabolismo , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Comportamento Estereotipado/efeitos dos fármacos
16.
QJM ; 102(4): 271-82, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19174502

RESUMO

BACKGROUND: There are currently no field data about the effect of implementing European Working Time Directive (EWTD)-compliant rotas in a medical setting. Surveys of doctors' subjective opinions on shift work have not provided reliable objective data with which to evaluate its efficacy. AIM: We therefore studied the effects on patient's safety and doctors' work-sleep patterns of implementing an EWTD-compliant 48 h work week in a single-blind intervention study carried out over a 12-week period at the University Hospitals Coventry & Warwickshire NHS Trust. We hypothesized that medical error rates would be reduced following the new rota. METHODS: Nineteen junior doctors, nine studied while working an intervention schedule of <48 h per week and 10 studied while working traditional weeks of <56 h scheduled hours in medical wards. Work hours and sleep duration were recorded daily. Rate of medical errors (per 1000 patient-days), identified using an established active surveillance methodology, were compared for the Intervention and Traditional wards. Two senior physicians blinded to rota independently rated all suspected errors. RESULTS: Average scheduled work hours were significantly lower on the intervention schedule [43.2 (SD 7.7) (range 26.0-60.0) vs. 52.4 (11.2) (30.0-77.0) h/week; P < 0.001], and there was a non-significant trend for increased total sleep time per day [7.26 (0.36) vs. 6.75 (0.40) h; P = 0.095]. During a total of 4782 patient-days involving 481 admissions, 32.7% fewer total medical errors occurred during the intervention than during the traditional rota (27.6 vs. 41.0 per 1000 patient-days, P = 0.006), including 82.6% fewer intercepted potential adverse events (1.2 vs. 6.9 per 1000 patient-days, P = 0.002) and 31.4% fewer non-intercepted potential adverse events (16.6 vs. 24.2 per 1000 patient-days, P = 0.067). Doctors reported worse educational opportunities on the intervention rota. CONCLUSIONS: Whilst concerns remain regarding reduced educational opportunities, our study supports the hypothesis that a 48 h work week coupled with targeted efforts to improve sleep hygiene improves patient safety.


Assuntos
Erros Médicos/prevenção & controle , Admissão e Escalonamento de Pessoal/organização & administração , Transtornos do Sono do Ritmo Circadiano/prevenção & controle , Adulto , Atitude do Pessoal de Saúde , Feminino , Humanos , Masculino , Erros Médicos/estatística & dados numéricos , Projetos Piloto , Estudos Prospectivos , Reino Unido , Tolerância ao Trabalho Programado
17.
Rev Sci Instrum ; 79(11): 113105, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19045887

RESUMO

An instrument has been designed and constructed to provide new insights into fundamental, low energy positron scattering processes. The design is based on the Surko trap system and produces a pulsed positron beam with an energy resolution of as good as 54 meV. The design and operation of the apparatus is explained, while the first experimental results from this apparatus have been demonstrated in recent publications.

18.
J Evol Biol ; 21(4): 1030-45, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18513358

RESUMO

Mormyrid fishes produce and sense weak electric organ discharges (EODs) for object detection and communication, and they have been increasingly recognized as useful model organisms for studying signal evolution and speciation. EOD waveform variation can provide important clues to sympatric species boundaries between otherwise similar or morphologically cryptic forms. Endemic to the watersheds of Gabon (Central Africa), Ivindomyrus marchei and Ivindomyrus opdenboschi are morphologically similar to one another. Using morphometric, electrophysiological and molecular characters [cytochrome b sequences and amplified fragment length polymorphism (AFLP) genotypes], we investigated to what extent these nominal mormyrid species have diverged into biological species. Our sampling covered the known distribution of each species with a focus on the Ivindo River, where the two taxa co-occur. An overall pattern of congruence among datasets suggests that I. opdenboschi and I. marchei are mostly distinct. Electric signal analysis showed that EODs of I. opdenboschi tend to have a smaller initial head-positive peak than those of I. marchei, and they often possess a small third waveform peak that is typically absent in EODs of I. marchei. Analysis of sympatric I. opdenboschi and I. marchei populations revealed slight, but significant, genetic partitioning between populations based on AFLP data (F(ST) approximately 0.04). Taken separately, however, none of the characters we evaluated allowed us to discriminate two completely distinct or monophyletic groups. Lack of robust separation on the basis of any single character set may be a consequence of incomplete lineage sorting due to recent ancestry and/or introgressive hybridization. Incongruence between genetic datasets in one individual, which exhibited a mitochondrial haplotype characteristic of I. marchei but nevertheless fell within a genetic cluster of I. opdenboschi based on AFLP genotypes, suggests that a low level of recent hybridization may also be contributing to patterns of character variation in sympatry. Nevertheless, despite less than perfect separability based on any one dataset and inconclusive evidence for complete reproductive isolation between them in the Ivindo River, we find sufficient evidence to support the existence of two distinctive species, I. opdenboschi and I. marchei, even if not 'biological species' in the Mayrian sense.


Assuntos
Evolução Biológica , Peixe Elétrico/anatomia & histologia , Peixe Elétrico/genética , Elétrons , África Central , Animais , Citocromos b/genética , Citocromos b/metabolismo , Peixe Elétrico/classificação , Peixe Elétrico/metabolismo , Filogenia , Polimorfismo Genético/genética
19.
Br J Pharmacol ; 153(2): 390-401, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17994110

RESUMO

BACKGROUND AND PURPOSE: Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are mu-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist. EXPERIMENTAL APPROACH: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and mu-opioid receptor antagonists. KEY RESULTS: A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or mu-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. CONCLUSIONS AND IMPLICATIONS: These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain.


Assuntos
Analgésicos não Narcóticos/farmacologia , Ciclopropanos/farmacologia , Morfolinas/farmacologia , Dor/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Analgésicos não Narcóticos/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Células Cultivadas , Constrição Patológica/complicações , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Cicloexanóis/farmacologia , Ciclopropanos/uso terapêutico , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Imunossupressores/farmacologia , Articulações/patologia , Masculino , Microscopia de Fluorescência , Morfolinas/uso terapêutico , Atividade Motora/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Ciática/tratamento farmacológico , Ciática/etiologia
20.
J Neurosci ; 26(37): 9385-93, 2006 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-16971522

RESUMO

Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.


Assuntos
Analgésicos/farmacocinética , Sistema Nervoso Central/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Dor/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Analgésicos/metabolismo , Animais , Artralgia/tratamento farmacológico , Artralgia/metabolismo , Artralgia/fisiopatologia , Cálcio/metabolismo , Capsaicina/antagonistas & inibidores , Linhagem Celular , Células Cultivadas , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Indazóis/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Injeções Espinhais , Masculino , Nociceptores/metabolismo , Dor/metabolismo , Dor/fisiopatologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonas/farmacologia , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Resultado do Tratamento , Ureia/análogos & derivados , Ureia/farmacologia
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