Factors Mediating Alcohol Craving and Relapse: Stress, Compulsivity, and Genetics

This article represents the proceedings of a symposium at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany. The symposium was organized by Zachary A. Rodd and Giancarlo Colombo. The presentations were (1) Pharmacological reversal of cycled withdrawal-sensitized or stress-sensitized withdrawal anxiety and enhanced ethanol drinking, by Darin J. Knapp and George R. Breese, (2) Alcohol craving and relapse in rats genetically selected for high alcohol preference, by Zachary A. Rodd and Richard L. Bell, (3) Exposure to stress increases dopaminergic burst firing in awake rats, by Kristin Anstrom and Donald J. Woodward, (4) Involvement of cannabinoid CB1 and GABAB receptors in the control of relapse-like drinking in alcohol-preferring Sardinian alcohol-preferring rats by Giancarlo Colombo and Salvatore Serra, and (5) Stress-induced ethanol drinking in CB1−/−, POMC, and PENK knockout mice, by Idiko Racz and Andreas Zimmer

Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments

Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2−/− mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2−/− mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. © 2012 Neely et al

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species

Labour Law and Metaverse – can they fit together?

The paper focuses on some labour law questions which arise from work in the metaverse. The first question is whether meta-work could be the next new type of work as standard employment relationship, which is going through a transformation in general. Indeed, the idea of personal work – as a main pillar of the employment relationship – was challenged by platform work in the recent years, but metaverse seems to further question the old paradigms. The article shortly examines the question of wages, for instance, as the metaverse generally relies on cryptocurrency (CC) to pay for transactions and purchases. Subsequently, the paper mainly concentrates on the analysis of health and safety at work and of the discrimination ban in metaverse

The Effects of Percutaneous Coronary Intervention on the Flow in Acute Coronary Syndrome Patients—Geometry in Focus

Evaluation of the effect of three dimensional (3D) coronary plaque characteristics derived from two dimensional (2D) invasive angiography images (ICA) on coronary flow determined by TIMI frame count (TFC) in acute coronary syndrome (ACS) has not been thoroughly investigated. A total of 71 patients with STEMI, and 73 with NSTEMI were enrolled after primary angioplasty. Pre- and post-PCI TFCs were obtained. From 2D images, 3D reconstruction was performed of the culprit vessel, and multiple plaque parameters were measured. In STEMI, the average post-PCI frame count decreased significantly, resulting in better flow. With regards to 2/3D parameters, no differences were found between the STEMI and NSTEMI groups. The 3D parameters in the subgroup with an increase with at least three frames resulting in worsening post-PCI flow were compared to parameters of the patients with improved or significantly not change flow (delta frame count < 3), and greater minimal luminal diameter and area was found in the worsening (increased) frame group. In STEMI 2/3D, parameters showed no correlation with worsening flow, whereas in NSTEMI, greater minimal luminal diameter and area correlated with decreased flow. We can conclude that certain 2/3D parameters can predict slower flow in ACS, resulting in the use of GP IIb/IIIa receptor blocker

Modulation of the Ca²⁺ conductance of nicotinic acetylcholine receptors by Lypd6

The agonist binding sensitivity and desensitization kinetics of nicotinic acetylcholine receptors (nAChRs) can be modulated by snake venom neurotoxins and related endogenous small proteins of the uPAR-Ly6 family. Here we identify Lypd6, a distantly related member of the u-PAR/Ly-6 family expressed in neurons as a novel modulator of nAChRs. Lypd6 overexpressed in trigeminal ganglia neurons selectively enhanced the Ca²⁺-component of nicotine-evoked currents through nAChRs, as evidenced by comparative whole-cell patch clamp recordings and Ca²⁺-imaging in wildtype and transgenic mice overexpressing Lypd6. In contrast, a knockdown of Lypd6 expression using siRNAs selectively reduced nicotine-evoked Ca²⁺-currents. Pharmacological experiments revealed that the nAChRs involved in this process are heteromers. Transgenic mice displayed behaviors that were indicative of an enhanced cholinergic tone, such as a higher locomotor arousal, increased prepulse-inhibition and hypoalgesia. These mice overexpressing Lypd6 mice were also more sensitive to the analgesic effects of nicotine. Transgenic mice expressing siRNAs directed against Lypd6 were unable to procreate, thus indicating a vital role for this protein. Taken together, Lypd6 seems to constitute a novel modulator of nAChRs that affects receptor function by selectively increasing Ca²⁺-influx through this ion channels.12 page(s