53 research outputs found
P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.
Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.This work was supported by The Medical Research Council (D.C.B.), a Wellcome Trust University Award (L.A.B.), Neusentis (D.C.B.), The Royal College of Surgeons of England (G.B.), The Biotechnology and Biological Sciences Research Council (J.R.F.H.), Bowel & Cancer Research (M.A.T.), Pain Relief Foundation and Crohn's in Childhood Research Association (V.C.-G.), and The Dr Hadwen Trust for Humane Research (C.M.)
Functional and anatomical deficits in visceral nociception with age: a mechanism of silent appendicitis in the elderly?
The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and noninflamed appendixes were collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single-unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of calcitonin gene-related peptide-positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single-unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrate that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly
Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli.
Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9(-/-) mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in NaV1.9(-/-) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9(-/-) mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics
Background Determination for the LUX-ZEPLIN (LZ) Dark Matter Experiment
The LUX-ZEPLIN experiment recently reported limits on WIMP-nucleus
interactions from its initial science run, down to cm
for the spin-independent interaction of a 36 GeV/c WIMP at 90% confidence
level. In this paper, we present a comprehensive analysis of the backgrounds
important for this result and for other upcoming physics analyses, including
neutrinoless double-beta decay searches and effective field theory
interpretations of LUX-ZEPLIN data. We confirm that the in-situ determinations
of bulk and fixed radioactive backgrounds are consistent with expectations from
the ex-situ assays. The observed background rate after WIMP search criteria
were applied was events/keV/kg/day in the
low-energy region, approximately 60 times lower than the equivalent rate
reported by the LUX experiment.Comment: 25 pages, 15 figure
A search for new physics in low-energy electron recoils from the first LZ exposure
The LUX-ZEPLIN (LZ) experiment is a dark matter detector centered on a
dual-phase xenon time projection chamber. We report searches for new physics
appearing through few-keV-scale electron recoils, using the experiment's first
exposure of 60 live days and a fiducial mass of 5.5t. The data are found to be
consistent with a background-only hypothesis, and limits are set on models for
new physics including solar axion electron coupling, solar neutrino magnetic
moment and millicharge, and electron couplings to galactic axion-like particles
and hidden photons. Similar limits are set on weakly interacting massive
particle (WIMP) dark matter producing signals through ionized atomic states
from the Migdal effect.Comment: 13 pages, 10 figures. See https://tinyurl.com/LZDataReleaseRun1ER for
a data release related to this pape
First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment
The LUX-ZEPLIN (LZ) experiment is a dark matter detector centered on a
dual-phase xenon time projection chamber operating at the Sanford Underground
Research Facility in Lead, South Dakota, USA. This Letter reports results from
LZ's first search for Weakly Interacting Massive Particles (WIMPs) with an
exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood
ratio analysis shows the data to be consistent with a background-only
hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent
WIMP-neutron, and spin-dependent WIMP-proton cross-sections for WIMP masses
above 9 GeV/c. The most stringent limit is set at 30 GeV/c, excluding
cross sections above 5.9 cm at the 90\% confidence level.Comment: 9 pages, 6 figures. See https://tinyurl.com/LZDataReleaseRun1 for a
data release related to this pape
A Next-Generation Liquid Xenon Observatory for Dark Matter and Neutrino Physics
The nature of dark matter and properties of neutrinos are among the mostpressing issues in contemporary particle physics. The dual-phase xenontime-projection chamber is the leading technology to cover the availableparameter space for Weakly Interacting Massive Particles (WIMPs), whilefeaturing extensive sensitivity to many alternative dark matter candidates.These detectors can also study neutrinos through neutrinoless double-beta decayand through a variety of astrophysical sources. A next-generation xenon-baseddetector will therefore be a true multi-purpose observatory to significantlyadvance particle physics, nuclear physics, astrophysics, solar physics, andcosmology. This review article presents the science cases for such a detector.<br
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