Hypertensive effect of downregulation of the opioid system in mouse model of different activity of the endogenous opioid system

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development

6-Acetyl-5-hydroxy-4,7-dimethylcoumarin derivatives : design, synthesis, modeling studies, 5-HT1A, 5-HT2A and D2 receptors affinity

Molecular docking studies using appropriate 5-HT$_{1A}$, 5-HT$_{2A}$ and D$_{2}$ receptors models were used to design sixteen new 5-hydroxycoumarin derivatives with piperazine moiety (3–18). The microwave radiation have been used to synthesize them and their structures have been confirmed using mass spectrometry, $^{1}$H and $^{13}$C NMR. All newly prepared derivatives were evaluated for their 5-HT$_{1A}$, 5-HT$_{2A}$ and D$_{2}$ receptor affinity. Seven of the synthesized derivatives showed very high affinities to 5-HT$_{1A}$ receptor (3–4.0 nM, 6–4.0 nM, 7–1.0 nM, 9–6.0 nM, 15–4.3 nM, 16–1.0 nM, 18–3.0 nM) and one of them showed high affinities to 5-HT$_{2A}$ receptor (16–8.0 nM). In the case of the D$_{2}$ receptor none of the tested derivatives showed high affinity. Compounds 7 and 16 were identified as potent antagonists of the 5-HT$_{1A}$ receptor as shown by the [35S]GTPcS binding assay but they didn’t show any antidepressant effect at the single dose tested (10 mg/kg) in the tail suspension tests

The role of opioid receptor antagonists in regulation of blood pressure and T-cell activation in mice selected for high analgesia induced by swim stress

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone—an opioid antagonist—may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail–cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of μ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of μ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the μ opioid receptor increased the CD8 effector and central memory T-cell populations

Functional significance of transcripts editing by double-stranded RNA adenosine deaminases

Adenosine deaminases that act on RNA (ADARs) convert adenosine to inosine in double-stranded regions of RNA via hydrolytic deamination. As inosines are recognized as guanosines during translation this editing event can lead to a codon exchange in the edited mRNA. The amino acid changes introduced by this A-to-I RNA editing result in significant alterations in the physiological properties of gene products. For instance, editing of the "Q/R" site of AMPA GluR-B subunit dramatically decreases the Ca+2 permeability of the channel. Dramatic changes in the G-protein coupling efficiency of 5-HT2CR as well as in the rates of KV2K1 channel closure have been reported to be consequences of A-to-I RNA editing also. In addition, creation of an alternative splice acceptor site via editing of its own mRNA by ADAR2 has been reported. The A-to-I RNA editing mechanism requires: (1) a doublestranded RNA (dsRNA) structure, usually formed between the exonic editing site and a downstream intron sequence and (2) dsRNA-specific adenosine deaminases. The members of this ADAR gene family appear to share structural similarity, containing two to three repeats of dsRNA-binding domains and a separate deaminase or catalytic domain. Defects in ADAR are a cause of some diseases, for example dyschromatosis symmetrica hereditaria

Organization and functions of Cajal bodies

There is much interest in recent years in the possible role of different nuclear bodies (NBs) in cellular functions. NBs include the well-characterized Cajal bodies (CBs; or coiled bodies), which were first described in vertebrate neurons by Ramón y Cajal nearly 100 years ago and since then demonstrated in a variety of organisms and cell types, including both animals and plants. Cajal bodies contain C snurposomes with their associated B snurposomes. Many discussions of CB function emphasize their possible involvement in assembly, modification, or storage of RNA processing factors, especially small nucleolar ribonucleoprotein particles (snoRNPs), splicing small nuclear ribonucleoprotein particles (snRNPs), and the U7 snRNP. Moreover, some evidence suggests that CBs play an even wider role in transcription. Taking into account the composition of CBs and the targeting of various transcription and processing factors to CBs, we conclude that theymay be the primary site for assembly of the transcription machinery of the nucleus. The objective of this article is to summarize some aspects of these nuclear bodies, including their proposed roles in cells and in human diseases

An Update on the Evolutionary History of Bregs

The relationship between the evolutionary history and the differentiation of Bregs is still not clear. Bregs were demonstrated to possess a regulatory effect on B cells. Various subsets of Bregs have been identified including T2-MZP, MZ, B10, IL10-producing plasma cells, IL10 producing plasmablasts, immature IL10 producing B cells, TIM1, and Br1. It is known that B cells have evolved during fish emergence. However, the origin of Bregs is still not known. Three main models have been previously proposed to describe the origin of Bregs, the first known as single–single (SS) suggests that each type of Bregs subpopulation has emerged from a single pre-Breg type. The second model (single–multi) (SM) assumes that a single Bregs gave rise to multiple types of Bregs that in turn differentiated to other Breg subpopulations. In the third model (multi–multi) (MM), it is hypothesized that Bregs arise from the nearest B cell phenotype. The link between the differentiation of cells and the evolution of novel types of cells is known to follow one of three evolutionary patterns (i.e., homology, convergence, or concerted evolution). Another aspect that controls differentiation and evolution processes is the principle of optimization of energy, which suggests that an organism will always use the choice that requires less energy expenditure for survival. In this review, we investigate the evolution of Breg subsets. We studied the feasibility of Breg origination models based on evolution and energy constraints. In conclusion, our review indicates that Bregs are likely to have evolved under a combination of SM–MM models. This combination ensured successful survival in harsh conditions by following the least costly differentiation pathway, as well as adapting to changing environmental conditions

Review of research on alcohol dependence in a model of mice selected for high and low stress-induced analgesia

Decades of studies on alcohol dependence showed that it is a very complex and multifactorial disorder. Several receptor systems are involved in development and susceptibility to alcohol abuse; however, there are some which play a crucial role in its pathogenesis, e.g. dopaminergic or opioid system. In this paper, an effort is made to explain the role of endogenous opioid system activity in alcohol dependence. To achieve the goal, we use a unique model is used which shows mice lines that are divergently selected for high (HA) and low (LA) stress-induced analgesia. This process allowed for selecting individuals characterised by hyperactive (HA) or hypoactive (LA) opioid system. Basing on the performed experiments, we proved that delta opioid receptors play a critical role in the development of addiction. The most notable achievement is an unspecific reaction of mice with the hyperactive opioid system to naloxone – an unspecific opioid system antagonist, which is currently approved in the pharmacotherapy of dependent patients

Cytogenetic and genetic study of a Y-linked microsatellite polymorphism in Polish Black-and-White cattle breed

The aim of the current study was to characterize Polish Black-and-White cattle by morphological study of the Y chromosome. A total of 14 Y-linked microsatellites from UMN and INRA group were genotyped and assessed for polymorphism in a total 22 bulls. Cytogenetic studies in Polish Black-and-White bulls showed the existence of two morphological forms of Y chromosome. Among the 22 karyotypic analyzed bulls, 12 had submetacentric and 10 metacentric Y chromosome. The centromeric index of Y chromosome measured as percentage length of the p arm to total length ratio in the first case was 28 ± 3.97% and in the second 47 ± 7.28%, whereas the relative size of these chromosomes remained within the same range. Morphology and G- and C-banding patterns of both forms of Y chromosome were typical for other cattle breeds originating from Bos taurus. Out of a total of 14 microsatellite loci examined, 13 showed specific alleles for two forms of Y chromosome. In a pool of 62 alleles, 43 (69.3%) were common in the two groups of cattle, 19 (30.7%) can be considered as specific for the group; among them 8 were typical for metacentric group of Y chromosome and 11 for submetacentric. Keywords: Y chromosome, Microsatellite markers, Polymorphism, Polish Black-and-White cattl

Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine

The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine. (C) 2016 Elsevier B.V. All rights reserved