Sozialistische Stadt“ versus „europäische Stadt“ –: Urbanisierung und Ruralisierung im östlichen Europa

The „Socialist city“ versus the „European city“ – urbanization and ruralization in Eastern Europe In most parts of Eastern Europe the transition from agrarian to industrial societies took place only after World War II. The process of urbanization was influenced by the socialist planning economy. Under this condition, the concept of the “socialist city” found its realization in the modern reconstruction of old historical towns and the foundation of new industrial towns. Today the image of Eastern European capitals consists of monumental centers and monotonous neighborhoods. The development, however, leading to this dichotomy was the result of a lot of contradictions. On the one side, there was a lack of civil society already before the communist seize of power. On the other side, the exodus from the countryside during the period of socialist industrialization lead to a ruralization of already existing cities. At the end the “socialist city” was able to supply its inhabitants with a minimum of dwelling. But it still required the renunciation of urbanity and autonomy

Geschichte und Politik.: Makedonien im Kalkül des russischen Historikers und Dumaabgeordneten Pavel N. Miljukov

Four out of the seven chapters of the Carnegie Report on the Balkan Wars were written by Pavel N. Miliukov, a Russian historian and deputy of the Russian parliament. During his long travels in the Balkans between the end of the 19th century and the First World War, Miliukov had fulfilled duties of a researcher, a journalist and a politician. Having lectured at the University of Sofia, he left Bulgaria to take part in archaeological expeditions in Macedonia. In liberal Russian newspapers, he later wrote regularly about the current political situations in South-Eastern Europe. As a historian, Miliukov backed up Bulgaria in the struggle over the Macedonian question by relying on ethnological reasons. As a journalist, he initially preferred the establishment of a Balkan union that included the Ottoman Empire and then advocated the formation of a Balkan federation against the Young Turks. As a politician, he defended the national interests of Russia at the Bosporus and Dardanelles, which also went hand in hand with a Bulgarian predominance in the Balkans. Contrary to Miliukov’s articles in newspapers or his speeches in the parliament, his contributions to the Carnegie Report miss analytical insights. Miliukov defended the Bulgarian position in the Balkans by condemning the Treaty of Bucharest, which was signed in the aftermath of the Second Balkan War, and regarding it as a source of new conflicts.&nbsp

Antinociceptive Effects of Herkinorin, a MOP Receptor Agonist Derived from Salvinorin A in the Formalin Test in Rats: New Concepts in Mu Opioid Receptor Pharmacology

Herkinorin is the first μ opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of β-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin’s antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinociceptive effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states

Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

The kappa opioid receptor (KOR) is involved in mediating pruritus; agonists targeting this receptor have been used to treat chronic intractable itch. Conversely, antagonists induce an inch response at the site of injection. As a G protein-coupled receptor (GPCR), the KOR has potential for signaling via G proteins and βarrestins, however, it is not clear which of these pathways are involved in the KOR modulation of itch. In this study asked whether the actions of KOR in pruritus involve βarrestins by using βarrestin2 knockout (βarr2-KO) mice as well as a recently described biased KOR agonist that biases receptor signaling toward G protein pathways over βarrestin2 recruitment. We find that the KOR antagonists nor-binaltorphimine (NorBNI) and 5′-guanidinonaltrindole (5′GNTI) induce acute pruritus in C57BL/6J mice, with reduced effects in KOR-KO mice. βarr2-KO mice display less of a response to KOR antagonist-induced itch compared to wild types, however no genotype differences are observed from chloroquine phosphate (CP)-induced itch, suggesting that the antagonists may utilize a KOR-βarrestin2 dependent mechanism. The KOR agonist U50,488H was equally effective in both WT and βarr2-KO mice in suppressing CP-induced itch. Furthermore, the G protein biased agonist, Isoquinolinone 2.1 was as effective as U50,488H in suppressing the itch response induced by KOR antagonist NorBNI or CP in C57BL/6J mice. Together these data suggest that the antipruritic effects of KOR agonists may not require βarrestins

Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting

Differential modulation of kappa opioid receptor (KOR) signaling has been a proposed strategy for developing therapies for drug addiction and depression by either activating or blocking this receptor. Hence, there have been significant efforts to generate ligands with diverse pharmacological properties including partial agonists, antagonists, allosteric modulators as well as ligands that selectively activate some pathways while not engaging others (biased agonists). It is becoming increasingly evident that G protein coupled receptor signaling events are context dependent and that what may occur in cell based assays may not be fully indicative of signaling events that occur in the naturally occurring environment. As new ligands are developed, it is important to assess their signaling capacity in relevant endogenous systems in comparison to the performance of endogenous agonists. Since KOR is considered the cognate receptor for dynorphin peptides we have evaluated the selectivity profiles of dynorphin peptides in wild-type (WT), KOR knockout (KOR-KO), and mu opioid receptor knockout (MOR-KO) mice using [35S]GTPγS binding assay in striatal membrane preparations. We find that while the small molecule KOR agonist U69,593, is very selective for KOR, dynorphin peptides promiscuously stimulate G protein signaling in striatum. Furthermore, our studies demonstrate that norBNI and 5′GNTI are highly nonselective antagonists as they maintain full potency and efficacy against dynorphin signaling in the absence of KOR. Characterization of a new KOR antagonist, which may be more selective than NorBNI and 5′GNTI, is presented using this approach

Structure–Activity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1/2 Phosphorylation While Preserving G Protein Over βArrestin2 Signaling Bias

Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure–activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling