Facilitation of Serotonin-Induced Signaling by the Migraine Mediator CGRP in Rat Trigeminal Neurons

© 2016, Springer Science+Business Media New York.The monoamine neurotransmitter serotonin (5-HT) and the neuropeptide calcitonin gene-related peptide (CGRP) play an important role in migraine pathophysiology. To study potential interplay between 5-HT and CGRP in peripheral trigeminal nociception, we performed calcium imagining and patch clamp studies in rat trigeminal ganglia cells. We found that 5-HT activated Ca2+ transients in 18 % of trigeminal ganglia neurons. Exposure of trigeminal cells to CGRP significantly increased the number of 5-HT positive cells to 35 % and increased the amplitude of 5-HT-induced Ca2+ transients. Using patch clamp technique, we show that 37 % percent of trigeminal cells generated desensitizing membrane currents suggesting functional expression of 5-HT3 receptors. These responses were partially co-localized either with ATP-gated or capsaicin-sensitive neurons. Exposure to CGRP for 2 h increased the current density in the ATP-sensitive fraction of trigeminal neurons. Taken together, these data suggest that 5-HT receptor sensitization contributes to the pro-nociceptive effect of CGRP in trigeminal neurons

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

© 2016, Springer Science+Business Media Dordrecht.Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca2+ transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain

Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain

Serotonergic mechanisms play a central role in migraine pathology. However, the region-specific effects of serotonin (5-HT) mediated via multiple types of receptors in the nociceptive system are poorly understood. Using extracellular and patch-clamp recordings, we studied the action of 5-HT on the excitability of peripheral and central terminals of trigeminal afferents. 5-HT evoked long-lasting TTX-sensitive firing in the peripheral terminals of meningeal afferents, the origin site of migraine pain. Cluster analysis revealed that in majority of nociceptive fibers 5-HT induced either transient or persistent spiking activity with prevailing delta and theta rhythms. The 5-HT3-receptor antagonist MDL-72222 or 5-HT1B/D-receptor antagonist GR127935 largely reduced, but their combination completely prevented the excitatory pro-nociceptive action of 5-HT. The 5-HT3 agonist mCPBG activated spikes in MDL-72222-dependent manner but the 5HT-1 receptor agonist sumatriptan did not affect the nociceptive firing. 5-HT also triggered peripheral CGRP release in meninges, which was blocked by MDL-72222.5-HT evoked fast membrane currents and Ca2+ transients in a fraction of trigeminal neurons. Immunohistochemistry showed expression of 5-HT3A receptors in fibers innervating meninges. Endogenous release of 5-HT from degranulated mast cells increased nociceptive firing. Low pH but not histamine strongly activated firing. 5-HT reduced monosynaptic inputs from trigeminal Aδ- and C-afferents to the upper cervical lamina I neurons and this effect was blocked by MDL-72222. Consistent with central inhibitory effect, 5-HT reduced CGRP release in the brainstem slices. In conclusion, 5-HT evokes powerful pro-nociceptive peripheral and anti-nociceptive central effects in trigeminal system transmitting migraine pain.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The study was supported by the Finnish Academy (grant 277442). AZ was supported by the subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities and the Government of the Russian Federation (grant No.11.G34.31.0075). The work of IS was supported by RFBR grant 14-04-00885. BVS was supported by the grant from the Fundacao para a Ciencia e a Tecnologia (PTDC/NEU-NMC/1259/2014) and from the programme NORTE 2020

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Magnetic fields inferred by Solar Orbiter: A comparison between SO/PHI-HRT and SDO/HMI

The High Resolution Telescope (HRT) of the Polarimetric and Helioseismic Imager on board the Solar Orbiter spacecraft (SO/PHI) and the Helioseismic and Magnetic Imager (HMI) on board the Solar Dynamics Observatory (SDO) both infer the photospheric magnetic field from polarised light images. SO/PHI is the first magnetograph to move out of the Sun--Earth line and will provide unprecedented access to the Sun's poles. This provides excellent opportunities for new research wherein the magnetic field maps from both instruments are used simultaneously. We aim to compare the magnetic field maps from these two instruments and discuss any possible differences between them. We used data from both instruments obtained during Solar Orbiter's inferior conjunction on 7 March 2022. The HRT data were additionally treated for geometric distortion and degraded to the same resolution as HMI. The HMI data were re-projected to correct for the $3^{\circ}$ separation between the two observatories. SO/PHI-HRT and HMI produce remarkably similar line-of-sight magnetograms, with a slope coefficient of $0.97$, an offset below $1$ G, and a Pearson correlation coefficient of $0.97$. However, SO/PHI-HRT infers weaker line-of-sight fields for the strongest fields. As for the vector magnetic field, SO/PHI-HRT was compared to both the $720$-second and $90$-second HMI vector magnetic field: SO/PHI-HRT has a closer alignment with the $90$-second HMI vector. In the weak signal regime ($< 600$ G), SO/PHI-HRT measures stronger and more horizontal fields than HMI, very likely due to the greater noise in the SO/PHI-HRT data. In the strong field regime ($\gtrsim 600$ G), HRT infers lower field strengths but with similar inclinations (a slope of $0.92$) and azimuths (a slope of $1.02$). The slope values are from the comparison with the HMI $90$-second vector.Comment: 10 pages, 5 figures, accepted for publication in A&A; manuscript is a part of Astronomy & Astrophysics special issue: Solar Orbiter First Results (Nominal Mission Phase

Wavefront error of PHI/HRT on Solar Orbiter at various heliocentric distances

We use wavefront sensing to characterise the image quality of the the High Resolution Telescope (HRT) of the Polarimetric and Helioseismic Imager (SO/PHI) data products during the second remote sensing window of the Solar Orbiter (SO) nominal mission phase. Our ultimate aims are to reconstruct the HRT data by deconvolving with the HRT point spread function (PSF) and to correct for the effects of optical aberrations on the data. We use a pair of focused--defocused images to compute the wavefront error and derive the PSF of HRT by means of a phase diversity (PD) analysis. The wavefront error of HRT depends on the orbital distance of SO to the Sun. At distances $>0.5$\,au, the wavefront error is small, and stems dominantly from the inherent optical properties of HRT. At distances $<0.5$\,au, the thermo-optical effect of the Heat Rejection Entrance Window (HREW) becomes noticeable. We develop an interpolation scheme for the wavefront error that depends on the thermal variation of the HREW with the distance of SO to the Sun. We also introduce a new level of image reconstruction, termed `aberration correction', which is designed to reduce the noise caused by image deconvolution while removing the aberrations caused by the HREW. The computed PSF via phase diversity significantly reduces the degradation caused by the HREW in the near-perihelion HRT data. In addition, the aberration correction increases the noise by a factor of only $1.45$ compared to the factor of $3$ increase that results from the usual PD reconstructions

Stereoscopic disambiguation of vector magnetograms: first applications to SO/PHI-HRT data

Spectropolarimetric reconstructions of the photospheric vector magnetic field are intrinsically limited by the 180$^\circ$-ambiguity in the orientation of the transverse component. So far, the removal of such an ambiguity has required assumptions about the properties of the photospheric field, which makes disambiguation methods model-dependent. The basic idea is that the unambiguous line-of-sight component of the field measured from one vantage point will generally have a non-zero projection on the ambiguous transverse component measured by the second telescope, thereby determining the ``true'' orientation of the transverse field. Such an idea was developed and implemented in the Stereoscopic Disambiguation Method (SDM), which was recently tested using numerical simulations. In this work we present a first application of the SDM to data obtained by the High Resolution Telescope (HRT) onboard Solar Orbiter during the March 2022 campaign, when the angle with Earth was 27 degrees. The method is successfully applied to remove the ambiguity in the transverse component of the vector magnetogram solely using observations (from HRT and from the Helioseismic and Magnetic Imager), for the first time. The SDM is proven to provide observation-only disambiguated vector magnetograms that are spatially homogeneous and consistent. A discussion about the sources of error that may limit the accuracy of the method, and of the strategies to remove them in future applications, is also presented.Comment: 32 pages, 12 figures, accepted in A&A on 09/07/202

The ratio of horizontal to vertical displacement in solar oscillations estimated from combined SO/PHI and SDO/HMI observations

In order to make accurate inferences about the solar interior using helioseismology, it is essential to understand all the relevant physical effects on the observations. One effect to understand is the (complex-valued) ratio of the horizontal to vertical displacement of the p- and f-modes at the height at which they are observed. Unfortunately, it is impossible to measure this ratio directly from a single vantage point, and it has been difficult to disentangle observationally from other effects. In this paper we attempt to measure the ratio directly using 7.5 hours of simultaneous observations from the Polarimetric and Helioseismic Imager on board Solar Orbiter and the Helioseismic and Magnetic Imager on board the Solar Dynamics Observatory. While image geometry problems make it difficult to determine the exact ratio, it appears to agree well with that expected from adiabatic oscillations in a standard solar model. On the other hand it does not agree with a commonly used approximation, indicating that this approximation should not be used in helioseismic analyses. In addition, the ratio appears to be real-valued.Comment: Accepted for publication in Astronomy & Astrophysics. 8 pages, 8 figure