Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.

• Klíčová slova
• Aging, NOP, Senescence, Senolytic,
• MeSH
• anxiolytika * farmakologie   MeSH
• Caenorhabditis elegans MeSH
• léky proti stárnutí * MeSH
• lidé MeSH
• ligandy MeSH
• myši MeSH
• narkotika - antagonisté farmakologie   MeSH
• nociceptin MeSH
• opioidní analgetika MeSH
• opioidní peptidy MeSH
• piperidiny farmakologie   MeSH
• receptory opiátové MeSH
• rychlé screeningové testy MeSH
• stárnutí buněk * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anxiolytika * MeSH
• léky proti stárnutí * MeSH
• ligandy MeSH
• narkotika - antagonisté MeSH
• opioidní analgetika MeSH
• opioidní peptidy MeSH
• piperidiny MeSH
• receptory opiátové MeSH

The role of opioid kappa1 and kappa2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid kappa receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 - 48% in untreated rats. Administration of the opioid kappa1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42%. Administration of the opioid kappa receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41%. The non-selective opioid kappa receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid kappa receptor, the peripherally acting opioid kappa2 receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid ?2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally acting opioid receptor antagonist naloxone methiodide, or the selective opioid kappa2 receptor antagonist nor-binaltorphimine completely abolished the infarct-reducing effect of (-)-U-50,488 and ICI 199,441. Pretreatment with the selective opioid ? receptor antagonist TIPP[psi] and the selective opioid µ receptor antagonist CTAP did not alter the infarct reducing effect of (-)-U-50,488 and ICI 199,441. Our study is the first to demonstrate the following: (a) the activation of opioid kappa2 receptor has no effect on cardiac tolerance to reperfusion; (b) peripheral opioid kappa1 receptor stimulation prevents reperfusion cardiac injury; (c) ICI 199,441 administration resulted in an infarct-reducing effect at reperfusion; (e) bradycardia induced by opioid kappa receptor antagonists is not dependent on the occupancy of opioid kappa receptor.

• MeSH
• 3,4-dichlor-N-methyl-N-(2-(1-pyrrolidinyl)-cyklohexyl)-benzenacetamid, (trans)-isomer aplikace a dávkování   toxicita   MeSH
• infarkt myokardu metabolismus   patologie   prevence a kontrola   MeSH
• intravenózní podání MeSH
• kardiomyocyty účinky léků   metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• narkotika - antagonisté aplikace a dávkování   MeSH
• opioidní analgetika aplikace a dávkování   toxicita   MeSH
• piperaziny aplikace a dávkování   MeSH
• potkani Wistar MeSH
• pyrrolidiny aplikace a dávkování   toxicita   MeSH
• receptory opiátové kappa agonisté   metabolismus   MeSH
• reperfuzní poškození myokardu metabolismus   patologie   prevence a kontrola   MeSH
• signální transdukce MeSH
• srdeční arytmie chemicky indukované   patofyziologie   MeSH
• srdeční frekvence účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• 3,4-dichlor-N-methyl-N-(2-(1-pyrrolidinyl)-cyklohexyl)-benzenacetamid, (trans)-isomer MeSH
• GR 89696 MeSH Prohlížeč
• ICI 199441 MeSH Prohlížeč
• kappa(1) opioid receptor MeSH Prohlížeč
• kappa(2) opioid receptor MeSH Prohlížeč
• narkotika - antagonisté MeSH
• opioidní analgetika MeSH
• piperaziny MeSH
• pyrrolidiny MeSH
• receptory opiátové kappa MeSH

The receptor channel transient receptor potential vanilloid 1 (TRPV1) functions as a sensor of noxious heat and various chemicals. There is increasing evidence for a crosstalk between TRPV1 and opioid receptors. Here we investigated the effect of the prototypical TRPV1 agonist capsaicin and selected opioid ligands on TRPV1 movement in the plasma membrane and intracellular calcium levels in HEK293 cells expressing TRPV1 tagged with cyan fluorescent protein (CFP). We observed that lateral mobility of TRPV1 increased after treatment of cells with capsaicin or naloxone (a nonselective opioid receptor antagonist) but not with DAMGO (a μ-opioid receptor agonist). Interestingly, both capsaicin and naloxone, unlike DAMGO, elicited intracellular calcium responses. The increased TRPV1 movement and calcium influx induced by capsaicin and naloxone were blocked by the TRPV1 antagonist capsazepine. The ability of naloxone to directly interact with TRPV1 was further corroborated by [3H]-naloxone binding. In conclusion, our data suggest that besides acting as an opioid receptor antagonist, naloxone may function as a potential TRPV1 agonist.

• Klíčová slova
• calcium, fluorescence recovery after photobleaching, naloxone, receptor lateral mobility, transient receptor potential vanilloid 1,
• MeSH
• buněčná membrána metabolismus   MeSH
• HEK293 buňky MeSH
• kapsaicin analogy a deriváty   farmakologie   MeSH
• kationtové kanály TRPV agonisté   genetika   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• naloxon farmakologie   MeSH
• narkotika - antagonisté farmakologie   MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kapsaicin MeSH
• kationtové kanály TRPV MeSH
• ligandy MeSH
• naloxon MeSH
• narkotika - antagonisté MeSH
• TRPV1 protein, human MeSH Prohlížeč
• vápník MeSH

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and delta2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in isolated rat heart. In this study, we hypothesize that this cardioprotective effect of CNH is mediated by activation of µ and delta2 ORs and preservation of mitochondrial function. Hearts from rats adapted to CNH (12 % oxygen) for 3 weeks were extracted, perfused in the Langendorff mode and subjected to 45 min of global ischemia and 30 min of reperfusion. Intervention groups were pretreated for 10 min with antagonists for different OR types: naloxone (300 nmol/l), the selective delta OR antagonist TIPP(psi) (30 nmol/l), the selective delta1 OR antagonist BNTX (1 nmol/l), the selective delta2 OR antagonist naltriben (1 nmol/l), the selective peptide µ OR antagonist CTAP (100 nmol/l) and the selective delta OR antagonist nor-binaltorphimine (3 nmol/l). Creatine kinase activity in coronary effluent and cardiac contractile function were monitored to assess cardiac injury and functional impairment. Additionally, cardiac tissue was collected to measure ATP and to isolate mitochondria to measure respiration rate and calcium retention capacity. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the postischemic recovery of contractile function. Additionally, CNH improved mitochondrial state 3 and uncoupled respiration rates, ADP/O, mitochondrial transmembrane potential and calcium retention capacity and myocardial ATP level during reperfusion compared to the normoxic group. These protective effects were completely abolished by naloxone, TIPP(psi), naltriben, CTAP but not BNTX or nor-binaltorphimine. These results suggest that cardioprotection associated with adaptation to CNH is mediated by µ and delta2 opioid receptors activation and preservation of mitochondrial function.

• MeSH
• hypoxie patofyziologie   MeSH
• krysa rodu Rattus MeSH
• narkotika - antagonisté farmakologie   MeSH
• orgánové kultury - kultivační techniky MeSH
• potkani Wistar MeSH
• receptory opiátové delta antagonisté a inhibitory   fyziologie   MeSH
• receptory opiátové mu antagonisté a inhibitory   fyziologie   MeSH
• reperfuzní poškození myokardu patofyziologie   prevence a kontrola   MeSH
• srdeční mitochondrie účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DOR2 protein, rat MeSH Prohlížeč
• narkotika - antagonisté MeSH
• receptory opiátové delta MeSH
• receptory opiátové mu MeSH

Opiate addiction has a high rate of relapse. The accumulating evidence shows that electroacupuncture (EA) may be effective for the treatment of opiate relapse. However, the change of expression of CB1-Rs and CB2-Rs involve in 2Hz EA anti-relapse pathway is still unclear. To explore the changes of expression of CB1-Rs and CB2-Rs, heroin self-administration (SA) model rats were adopted and treated using 2Hz EA. The expressions of CB1-Rs and CB2-Rs were observed using immunohistochemistry method. The results showed that, compared with the control group, active pokes in the heroin-addicted group increased, while the active pokes decreased significantly in 2Hz EA group compared with heroin-addicted group. Correspondingly, the expression of CB1-Rs in prefrontal cortex (PFC), hippocampus (Hip), nucleus accumbens (NAc) and ventral tegmental area (VTA) all increased significantly while the expression of CB2-Rs in those relapse-relevant brain regions decreased obviously in heroin-addicted group when compared with the control group. In addition, the expression of CB1-Rs obviously decreased in the 2Hz EA group while the expression of CB2-Rs in those relapse-relevant brain regions increased significantly when compared with the heroin-addicted group. It indicated that 2Hz EA could attenuate the heroin-evoked seeking behaviors effectively. The anti-relapse effects of 2Hz EA might be related to the decrease of CB1-Rs and increase of CB2-Rs expression in relapse-relevant brain regions of heroin SA rats.

• MeSH
• autoaplikace MeSH
• chování při shánění drogy účinky léků   MeSH
• chování zvířat účinky léků   MeSH
• elektroakupunktura * MeSH
• extinkce (psychologie) účinky léků   MeSH
• heroin aplikace a dávkování   MeSH
• lokomoce účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• mozek účinky léků   metabolismus   patofyziologie   MeSH
• narkotika - antagonisté aplikace a dávkování   MeSH
• potkani Sprague-Dawley MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• receptor kanabinoidní CB2 metabolismus   MeSH
• recidiva MeSH
• signální transdukce MeSH
• závislost na heroinu metabolismus   patofyziologie   psychologie   terapie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Cnr1 protein, rat MeSH Prohlížeč
• Cnr2 protein, rat MeSH Prohlížeč
• heroin MeSH
• narkotika - antagonisté MeSH
• receptor kanabinoidní CB1 MeSH
• receptor kanabinoidní CB2 MeSH

The objectives of this study were to investigate the role of endogenous opioids in the mediation of stress-induced cardiomyopathy (SIC), and to evaluate which opioid receptors regulate heart resistance to immobilization stress. Wistar rats were subjected to 24 h immobilization stress. Stress-induced heart injury was assessed by 99mTc-pyrophosphate accumulation in the heart. The opioid receptor (OR) antagonists (naltrexone, NxMB - naltrexone methyl bromide, MR 2266, ICI 174.864) and agonists (DALDA, DAMGO, DSLET, U-50,488) were administered intraperitoneally prior to immobilization and 12 h after the start of stress. In addition, the selective micro OR agonists PL017 and DAMGO were administered intracerebroventricularly prior to stress. Finally pretreatment with guanethidine was used. Naltrexone did not alter the cardiac 99mTc-PP accumulation in stressed rats. NxMB aggravated stress-induced cardiomyopathy (P=0.005) (SIC). The selective micro OR agonist DALDA, which does not cross the blood-brain barrier, completely prevented (P=0.006) SIC. The micro OR agonist DAMGO exhibited weaker effect than DALDA. The selective delta ligand (DSLET) and kappa OR ligand (U-50,488) did not alter stress-induced 99mTc-pyrophosphate accumulation in the heart. Intracerebroventricular administration of the micro OR agonists aggravated SIC. Pretreatment with guanethidine abolished this effect (P=0.01). Guanethidine alone exhibited cardioprotective properties. A stimulation of central micro OR promotes an appearance of SIC. In contrast, stimulation of peripheral micro OR contributes to an increase in cardiac tolerance to stress.

• MeSH
• enkefalin, Ala(2)-MePhe(4)-Gly(5)- farmakologie   terapeutické užití   MeSH
• imobilizace škodlivé účinky   psychologie   MeSH
• kardiotonika farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• myokard metabolismus   MeSH
• naltrexon farmakologie   MeSH
• narkotika - antagonisté farmakologie   MeSH
• nemoci srdce chemicky indukované   metabolismus   prevence a kontrola   MeSH
• opioidní analgetika farmakologie   terapeutické užití   MeSH
• potkani Wistar MeSH
• psychický stres metabolismus   psychologie   MeSH
• receptory opiátové mu agonisté   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• enkefalin, Ala(2)-MePhe(4)-Gly(5)- MeSH
• kardiotonika MeSH
• naltrexon MeSH
• narkotika - antagonisté MeSH
• opioidní analgetika MeSH
• receptory opiátové mu MeSH

We studied the role of the delta, micro, and kappa opioid receptor (OR) subtypes in the cardioprotective effect of chronic continuous normobaric hypoxia (CNH) in the model of acute anoxia-reoxygenation of isolated cardiomyocytes. Adaptation of rats to CNH was performed by their exposure to atmosphere containing 12 % of O(2) for 21 days. Anoxia-reoxygenation of cardiomyocytes isolated from normoxic control rats caused the death of 51 % of cells and lactate dehydrogenase (LDH) release. Adaptation of rats to CNH resulted in the anoxia/reoxygenation-induced cardiomyocyte death of only 38 %, and reduced the LDH release by 25 %. Pre-incubation of the cells with either the non-selective OR (opioid receptor) blocker naloxone (300 nM/l), the delta OR antagonist TIPP(psi) (30 nM/l), the selective delta(2) OR antagonist naltriben (1 nM/l) or the micro OR antagonist CTAP (100 nM/l) for 25 minutes before anoxia abolished the reduction of cell death and LDH release afforded by CNH. The antagonist of delta(1) OR BNTX (1 nM/l) or the kappa OR antagonist nor-binaltorphimine (3 nM/l) did not influence the cytoprotective effects of CNH. Taken together, the cytoprotective effect of CNH is associated with the activation of the delta(2) and micro OR localized on cardiomyocytes.

• MeSH
• cytoprotekce účinky léků   fyziologie   MeSH
• hypoxie metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• mediátory zánětu antagonisté a inhibitory   metabolismus   MeSH
• náhodné rozdělení MeSH
• narkotika - antagonisté farmakologie   MeSH
• potkani Wistar MeSH
• receptory opiátové metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mediátory zánětu MeSH
• narkotika - antagonisté MeSH
• receptory opiátové MeSH

There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala2,N-MePhe4,Gly5-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2. Interestingly, cholesterol depletion strongly enhanced the ability of morphine to elevate receptor mobility but significantly reduced or even eliminated the effect of DAMGO and endomorphin-2, respectively. Moreover, the ability of DAMGO and endomorphin-2 to influence MOR-YFP movement was diminished by pertussis toxin treatment. The results obtained by agonist-stimulated [35S]GTPγS binding assays indicated that DAMGO exhibited higher efficacy than morphine and endomorphin-2 did and that the efficacy of DAMGO, contrary to the latter agonists, was enhanced by cholesterol depletion. Overall, our study provides clear evidence that biased MOR agonists diversely affect receptor mobility in plasma membranes as well as MOR/G protein coupling and that the regulatory effect of different ligands depends on the membrane cholesterol content. These findings help to delineate the fundamental properties of MOR regarding their interaction with biased MOR ligands and cognate G proteins.

• Klíčová slova
• Biased agonists *, Cholesterol *, FRAP *, G protein coupling *, μ-Opioid receptor *,
• MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• cholesterol nedostatek   MeSH
• enkefalin, Ala(2)-MePhe(4)-Gly(5)- metabolismus   farmakologie   MeSH
• FRAP MeSH
• guanosin 5'-O-(3-thiotrifosfát) metabolismus   MeSH
• HEK293 buňky MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• ligandy MeSH
• luminescentní proteiny genetika   metabolismus   MeSH
• morfin metabolismus   farmakologie   MeSH
• narkotika - antagonisté farmakologie   MeSH
• oligopeptidy metabolismus   farmakologie   MeSH
• pertusový toxin farmakologie   MeSH
• proteiny vázající GTP - alfa-podjednotky Gi-Go metabolismus   MeSH
• receptory opiátové mu agonisté   genetika   metabolismus   MeSH
• rekombinantní fúzní proteiny metabolismus   MeSH
• transfekce MeSH
• transport proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• bakteriální proteiny MeSH
• cholesterol MeSH
• endomorphin 2 MeSH Prohlížeč
• enkefalin, Ala(2)-MePhe(4)-Gly(5)- MeSH
• guanosin 5'-O-(3-thiotrifosfát) MeSH
• ligandy MeSH
• luminescentní proteiny MeSH
• morfin MeSH
• narkotika - antagonisté MeSH
• oligopeptidy MeSH
• pertusový toxin MeSH
• proteiny vázající GTP - alfa-podjednotky Gi-Go MeSH
• receptory opiátové mu MeSH
• rekombinantní fúzní proteiny MeSH
• yellow fluorescent protein, Bacteria MeSH Prohlížeč

Licit and illicit drug use in pregnant women constitutes a long lasting and serious problem worldwide. Information on long-term effects of maternal drug use on the child is limited. Nationwide registers provide a great potential to study short and long-term consequences for children exposed to licit and illicit drugs during pregnancy. We discuss this potential, with a special emphasis on exposure to methamphetamine, heroin and prescription drugs used for opioid maintenance treatment (OMT). We also discuss the advantages of register data and of merging such data from different regions. The Czech and Scandinavian registers are largely comparable and provide great opportunities to conduct innovative research. For instance, using Czech and Scandinavian cohorts we can compare groups with similar characteristics, such as mothers in OMT and mothers addicted to other drugs while also controlling for important confounding factors such as health and socio-economic status.

• Klíčová slova
• children, drug use, methamphetamine, national health registry, opioid maintenance treatment, pregnancy, registry-linkage study,
• MeSH
• dospělí MeSH
• heroin toxicita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methamfetamin toxicita   MeSH
• narkotika - antagonisté toxicita   MeSH
• novorozenec MeSH
• opiátová substituční terapie MeSH
• opioidní analgetika toxicita   MeSH
• poruchy spojené s užíváním psychoaktivních látek epidemiologie   MeSH
• registrace MeSH
• těhotenství MeSH
• výsledek těhotenství MeSH
• zakázané drogy MeSH
• zpožděný efekt prenatální expozice * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Skandinávie a severské státy epidemiologie   MeSH
• Názvy látek
• heroin MeSH
• methamfetamin MeSH
• narkotika - antagonisté MeSH
• opioidní analgetika MeSH
• zakázané drogy MeSH

According to a recent literature review on the opioid mechanism in eating disorders, we found that there is increasing reason to re-examine the treatment potential of naltrexone. The endogenous opioid system belongs to the important modulators of food intake. The eating disorders share many traits with substance dependence models. We present two case histories of time-limited naltrexone therapy to show that, in clinical practice, individualized indication may contribute to short-term improvement and to prediction of a different long-term treatment outcome.

• MeSH
• afekt účinky léků   MeSH
• alkoholismus komplikace   farmakoterapie   MeSH
• dospělí MeSH
• lidé MeSH
• naltrexon terapeutické užití   MeSH
• narkotika - antagonisté terapeutické užití   MeSH
• poruchy příjmu potravy komplikace   farmakoterapie   MeSH
• sebezhodnocení (psychologie) MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• naltrexon MeSH
• narkotika - antagonisté MeSH