The Fermi Large Area Telescope (LAT) First Source Catalog (1FGL) provided spatial, spectral, and temporal properties for a large number of gamma -ray sources using a uniform analysis method. After ...correlating with the most-complete catalogs of source types known to emit gamma rays, 630 of these sources are "unassociated" (i.e., have no obvious counterparts at other wavelengths). Here, we employ two statistical analyses of the primary gamma -ray characteristics for these unassociated sources in an effort to correlate their y-ray properties with the active galactic nucleus (AGN) and pulsar populations in 1FGL. Based on the correlation results, we classify 221 AGN-like and 134 pulsar-like sources in the 1FGL unassociated sources. The results of these source "classifications" appear to match the expected source distributions, especially at high Galactic latitudes. While useful for planning future multiwavelength follow-up observations, these analyses use limited inputs, and their predictions should not be considered equivalent to "probable source classes" for these sources. We discuss multiwavelength results and catalog cross-correlations to date, and provide new source associations for 229 Fermi-LAT sources that had no association listed in the 1FGL catalog. By validating the source classifications against these new associations, we find that the new association matches the predicted source class in ~80% of the sources.
Following its launch in 2008 June, the Fermi Gamma-ray Space Telescope (Fermi) began a sky survey in August. The Large Area Telescope (LAT) on Fermi in three months produced a deeper and better ...resolved map of the g-ray sky than any previous space mission. We present here initial results for energies above 100 MeV for the 205 most significant (statistical significance greater than ~10s) g-ray sources in these data. These are the best characterized and best localized point-like (i.e., spatially unresolved) g-ray sources in the early mission data.
In this work, we report the discovery with Fermi/LAT of γ-ray emission from three radio-loud narrow-line Seyfert 1 galaxies: PKS 1502+036 (z = 0.409), 1H 0323+342 (z = 0.061), and PKS 2004 – 447 (z = ...0.24). In addition to PMN J0948+0022 (z = 0.585), the first source of this type to be detected in γ rays, they may form an emerging new class of γ-ray active galactic nuclei (AGNs). Lastly, these findings can have strong implications on our knowledge about relativistic jets and the unified model of the AGN.
Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, ...many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (
panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.
Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for ...anti‐craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug‐induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid‐mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co‐express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the ‘anti‐reward’ effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction‐related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.
Linked Articles
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in ...depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine self-administration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.
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