Cellular prion protein protects from inflammatory and neuropathic pain

Cellular prion protein (PrPC) inhibits N-Methyl-D-Aspartate (NMDA) receptors. Since NMDA receptors play an important role in the transmission of pain signals in the dorsal horn of spinal cord, we thus wanted to determine if PrPC null mice show a reduced threshold for various pain behaviours

NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cab3.2 T-type calcium channels and activation of CB2 receptors

Background: T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund’s Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. Results: NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se, as evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV3.2 as a key target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo. Conclusions: Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/ T-type channel blockers

Analgesic Effect of a Mixed T-Type Channel Inhibitor/CB2 Receptor Agonist

Background: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. Results: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTP gamma[S-35] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Ca(V)3.2 currents with IC50 values in the low micromolar range and acted as a CB2 agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in Ca(V)3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB2 antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB1 antagonist). Conclusions: Our work shows that both T-type channels as well as CB2 receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T-type/cannabinoid receptor ligands

Quantitative Morphology of Galaxies from the SDSS I: Luminosity in Bulges and Disks

In the first paper of this series we use the publicly available code Gim2D to model the r- and i-band images of all galaxies in a magnitude-limited sample of roughly 1800 morphologically classified galaxies taken from the Sloan Digital Sky Survey. The model is a concentric superposition of two components, each with elliptical isophotes with constant flattening and position angle. The disk luminosity profile is assumed exponential, while the bulge is assumed to have a de Vaucouleurs or a Sersic profile. We find that the parameters returned by Gim2D depend little on the waveband or bulge profile used; their formal uncertainties are usually small. Nevertheless, for bright galaxies the measured distribution of b/a, the apparent disk flattening, deviates strongly from the expected uniform distribution, showing that the `disk' identified by the code frequently corresponds to an intrinsically 3-dimensional structure rather than to a true thin disk. We correct approximately for this systematic problem using the observed statistics of the b/a distribution and estimate, as a function of absolute magnitude, the mean fractions of galaxy light in disks and in `pure bulge' systems (those with no detectable disk). For the brightest galaxies the disk light fraction is about 10% and about 80% are `pure bulge' systems. For faint galaxies most of the light is in disks and we do not detect a `pure bulge' population. Averaging over the galaxy population as a whole, we find that 54 \pm 2% of the local cosmic luminosity density at both r and i comes from disks and 32 \pm 2% from `pure bulge' systems. The remaining 14 \pm 2% comes from bulges in galaxies with detectable disks.Comment: Submitted to MNRAS (14 pages, 14 figures). For version with higher quality figures, see http://www.mpa-garching.mpg.de/~tasca/MNRAS/Morph_paperI.p

Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands

<p>Abstract</p> <p>Background</p> <p>Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity.</p> <p>Results</p> <p>Novel compounds were characterized in radioligand binding assays and <it>in vitro </it>functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC₅₀values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response.</p> <p>Conclusions</p> <p>Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects <it>in vivo</it>. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.</p

Analytical expressions for the deprojected Sersic model

The Sersic model has become the standard to parametrize the surface brightness distribution of early-type galaxies and bulges of spiral galaxies. A major problem is that the deprojection of the Sersic surface brightness profile to a luminosity density cannot be executed analytically for general values of the Sersic index. Mazure & Capelato (2002) used the Mathematica computer package to derive an expression of the Sersic luminosity density in terms of the Meijer G function for integer values of the Sersic index. We generalize this work using analytical means and use Mellin integral transforms to derive an exact, analytical expression for the luminosity density in terms of the Fox H function for all values of the Sersic index. We derive simplified expressions for the luminosity density, cumulative luminosity and gravitational potential in terms of the Meijer G function for all rational values of the Sersic index and we investigate their asymptotic behaviour at small and large radii. As implementations of the Meijer G function are nowadays available both in symbolic computer algebra packages and as high-performance computing code, our results open up the possibility to calculate the density of the Sersic models to arbitrary precision.Comment: 9 pages, accepted for publication in Astronomy and Astrophysic

Mid-infrared Galaxy Morphology from the Spitzer Survey of Stellar Structure in Galaxies (S^4G): The Imprint of the De Vaucouleurs Revised Hubble-Sandage Classification System at 3.6 μm

Spitzer Space Telescope Infrared Array Camera imaging provides an opportunity to study all known morphological types of galaxies in the mid-IR at a depth significantly better than ground-based near-infrared and optical images. The goal of this study is to examine the imprint of the de Vaucouleurs classification volume in the 3.6 μm band, which is the best Spitzer waveband for galactic stellar mass morphology owing to its depth and its reddening-free sensitivity mainly to older stars. For this purpose, we have prepared classification images for 207 galaxies from the Spitzer archive, most of which are formally part of the Spitzer Survey of Stellar Structure in Galaxies (S^4G), a Spitzer post-cryogenic ("warm") mission Exploration Science Legacy Program survey of 2331 galaxies closer than 40 Mpc. For the purposes of morphology, the galaxies are interpreted as if the images are blue light, the historical waveband for classical galaxy classification studies. We find that 3.6 μm classifications are well correlated with blue-light classifications, to the point where the essential features of many galaxies look very similar in the two very different wavelength regimes. Drastic differences are found only for the most dusty galaxies. Consistent with a previous study by Eskridge et al., the main difference between blue-light and mid-IR types is an ≈1 stage interval difference for S0/a to Sbc or Sc galaxies, which tend to appear "earlier" in type at 3.6 μm due to the slightly increased prominence of the bulge, the reduced effects of extinction, and the reduced (but not completely eliminated) effect of the extreme population I stellar component. We present an atlas of all of the 207 galaxies analyzed here and bring attention to special features or galaxy types, such as nuclear rings, pseudobulges, flocculent spiral galaxies, I0 galaxies, double-stage and double-variety galaxies, and outer rings, that are particularly distinctive in the mid-IR

Stellar populations of bulges at low redshift

This chapter summarizes our current understanding of the stellar population properties of bulges and outlines important future research directions.Comment: Review article to appear in "Galactic Bulges", Editors: Laurikainen E., Peletier R., Gadotti D., Springer Publishing. 34 pages, 12 figure