Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ9-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.

• MeSH
• benzoxaziny * farmakologie   MeSH
• hyperalgezie * genetika   MeSH
• morfoliny farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované * MeSH
• myši MeSH
• naftaleny MeSH
• nocicepce účinky léků   MeSH
• receptor kanabinoidní CB1 * genetika   metabolismus   MeSH
• tetrahydrokanabinol * farmakologie   MeSH
• zánět * MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Three decades ago, the first endocannabinoid, anandamide (AEA), was identified, and its analgesic effect was recognized in humans and preclinical models. However, clinical trial failures pointed out the complexity of the AEA-induced analgesia. The first synapses in the superficial laminae of the spinal cord dorsal horn represent an important modulatory site in nociceptive transmission and subsequent pain perception. The glutamatergic synaptic transmission at these synapses is strongly modulated by two primary AEA-activated receptors, cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both highly expressed on the presynaptic side formed by the endings of primary nociceptive neurons. Activation of these receptors can have predominantly inhibitory (CB1) and excitatory (TRPV1) effects that are further modulated under pathological conditions. In addition, dual AEA-mediated signaling and action may occur in primary sensory neurons and dorsal horn synapses. AEA application causes balanced inhibition and excitation of primary afferent synaptic input on superficial dorsal horn neurons in normal conditions, whereas peripheral inflammation promotes AEA-mediated inhibition. This review focuses mainly on the modulation of synaptic transmission at the spinal cord level and signaling in primary nociceptive neurons by AEA via CB1 and TRPV1 receptors. Furthermore, the spinal analgesic effect in preclinical studies and clinical aspects of AEA-mediated analgesia are considered.

• MeSH
• endokanabinoidy * metabolismus   MeSH
• kationtové kanály TRPV metabolismus   MeSH
• kyseliny arachidonové * metabolismus   farmakologie   MeSH
• lidé MeSH
• mícha * metabolismus   účinky léků   MeSH
• nervový přenos * fyziologie   účinky léků   MeSH
• nocicepce fyziologie   účinky léků   MeSH
• nociceptory metabolismus   účinky léků   fyziologie   MeSH
• polynenasycené alkamidy * metabolismus   MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

• MeSH
• antipsychotika farmakologie   MeSH
• haloperidol farmakologie   MeSH
• kognitivní dysfunkce metabolismus   farmakoterapie   MeSH
• krysa rodu rattus MeSH
• kyselina kynurenová * metabolismus   MeSH
• methylazoxymethanolacetát * analogy a deriváty   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny farmakologie   MeSH
• potkani Sprague-Dawley * MeSH
• prefrontální mozková kůra * metabolismus   účinky léků   MeSH
• pyrazoly farmakologie   MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• schizofrenie * metabolismus   farmakoterapie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The Cannabis sativa plant has been used for centuries as a recreational drug and more recently in the treatment of patients with neurological or psychiatric disorders. In many instances, treatment goals include relief from posttraumatic disorders, anxiety, or to support treatment of chronic pain. Ligands acting on cannabinoid receptor 1 (CB1R) are also potential targets for the treatment of other health conditions. Using an evidence-based approach, pharmacological investigation of CB1R agonists is timely, with the aim to provide chronically ill patients relief using well-defined and characterized compounds from cannabis. Hexahydrocannabinol (HHC), currently available over the counter in many countries to adults and even children, is of great interests to policy makers, legal administrators, and healthcare regulators, as well as pharmacologists. Herein, we studied the pharmacodynamics of HHC epimers, which activate CB1R. We compared their key CB1R-mediated signaling pathway activities and compared them to the pathways activated by Δ9-tetrahydrocannabinol (Δ9-THC). We provide evidence that activation of CB1R by HHC ligands is only broadly comparable to those mediated by Δ9-THC, and that both HHC epimers have unique properties. Together with the greater chemical stability of HHC compared to Δ9-THC, these molecules have a potential to become a part of modern medicine.

• MeSH
• agonisté kanabinoidních receptorů farmakologie   MeSH
• HEK293 buňky MeSH
• kanabinol farmakologie   MeSH
• lidé MeSH
• myši MeSH
• receptor kanabinoidní CB1 * metabolismus   agonisté   MeSH
• signální transdukce * účinky léků   MeSH
• tetrahydrokanabinol * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Obesity is believed to be associated with a dysregulated endocannabinoid system which may reflect enhanced inflammation. However, reports of this in human white adipose tissue (WAT) are limited and inconclusive. Marine long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have anti-inflammatory actions and therefore may improve obesity-associated adipose tissue inflammation. Therefore, fatty acid (FA) concentrations, endocannabinoid concentrations, and gene expression were assessed in subcutaneous WAT (scWAT) biopsies from healthy normal weight individuals (BMI 18.5-25 kg/m2) and individuals living with metabolically healthy obesity (BMI 30-40 kg/m2) prior to and following a 12-week intervention with 3 g fish oil/day (1.1 g eicosapentaenoic acid (EPA) + 0.8 g DHA) or 3 g corn oil/day (placebo). WAT from individuals living with metabolically healthy obesity had higher n-6 PUFAs and EPA, higher concentrations of two endocannabinoids (anandamide (AEA) and eicosapentaenoyl ethanolamide (EPEA)), higher expression of phospholipase A2 Group IID (PLA2G2D) and phospholipase A2 Group IVA (PLA2G4A), and lower expression of CNR1. In response to fish oil intervention, WAT EPA increased to a similar extent in both BMI groups, and WAT DHA increased by a greater extent in normal weight individuals. WAT EPEA and docosahexaenoyl ethanolamide (DHEA) increased in normal weight individuals only and WAT 2-arachidonyl glycerol (2-AG) decreased in individuals living with metabolically healthy obesity only. Altered WAT fatty acid, endocannabinoid, and gene expression profiles in metabolically healthy obesity at baseline may be linked. WAT incorporates n-3 PUFAs when their intake is increased which affects the endocannabinoid system; however, effects appear greater in normal weight individuals than in those living with metabolically healthy obesity.

• MeSH
• časové faktory MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• endokanabinoidy metabolismus   MeSH
• fixní kombinace léků MeSH
• fosfolipasy A2, skupina II metabolismus   MeSH
• fosfolipasy A2, skupina IV metabolismus   MeSH
• kyselina eikosapentaenová aplikace a dávkování   MeSH
• kyseliny arachidonové metabolismus   MeSH
• kyseliny dokosahexaenové aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolicky zdravá obezita diagnóza   farmakoterapie   metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• podkožní tuk účinky léků   metabolismus   MeSH
• polynenasycené alkamidy metabolismus   MeSH
• potravní doplňky * MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Anglie MeSH

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

• MeSH
• endokanabinoidy metabolismus   MeSH
• ethanolaminy metabolismus   MeSH
• glyceridy metabolismus   MeSH
• hipokampus metabolismus   MeSH
• interpersonální vztahy MeSH
• kanabidiol farmakologie   MeSH
• krysa rodu rattus MeSH
• kyseliny arachidonové metabolismus   MeSH
• kyseliny olejové metabolismus   MeSH
• kyseliny palmitové metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• methylazoxymethanolacetát farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny farmakologie   MeSH
• pohybová aktivita účinky léků   MeSH
• polynenasycené alkamidy metabolismus   MeSH
• prefrontální mozková kůra metabolismus   MeSH
• puberta MeSH
• pyrazoly farmakologie   MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• rozpoznávání (psychologie) účinky léků   MeSH
• schizofrenie chemicky indukované   farmakoterapie   metabolismus   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype.

• MeSH
• acetylace MeSH
• antagonisté kanabinoidních receptorů farmakologie   MeSH
• antipsychotika farmakologie   MeSH
• časové faktory MeSH
• epigeneze genetická MeSH
• gestační stáří MeSH
• histondeacetylasa 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• histondeacetylasy genetika   metabolismus   MeSH
• histony metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• methylazoxymethanolacetát MeSH
• modely nemocí na zvířatech MeSH
• molekuly buněčné adheze nervové genetika   metabolismus   MeSH
• mozek účinky léků   embryologie   enzymologie   patologie   MeSH
• myši inbrední C57BL MeSH
• neurogeneze * účinky léků   MeSH
• neurony účinky léků   enzymologie   patologie   MeSH
• posttranslační úpravy proteinů MeSH
• potkani Sprague-Dawley MeSH
• receptor kanabinoidní CB1 antagonisté a inhibitory   metabolismus   MeSH
• schizofrenie chemicky indukované   farmakoterapie   enzymologie   genetika   MeSH
• signální transdukce MeSH
• transkripční faktory SOXB1 genetika   metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia.

• MeSH
• bipolární porucha genetika   metabolismus   MeSH
• CpG ostrůvky MeSH
• depresivní porucha unipolární genetika   metabolismus   MeSH
• endokanabinoidy metabolismus   MeSH
• kohortové studie MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methylazoxymethanolacetát MeSH
• metylace DNA * MeSH
• modely nemocí na zvířatech MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• receptor kanabinoidní CB1 genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• schizofrenie genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Many diseases of the nervous system are accompanied by alterations in synaptic functions. Synaptic plasticity mediated by the endogenous cannabinoid system involves the activation of the cannabinoid receptor 1 (CB1R). The principles of CB1R signaling must be understood in detail for its therapeutic exploration. We detected the Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1) as a novel CB1R partner. SGIP1 is functionally linked to clathrin-mediated endocytosis and its overexpression in animals leads to an energy regulation imbalance resulting in obesity. We report that SGIP1 prevents the endocytosis of activated CB1R and that it alters signaling via the CB1R in a biased manner. CB1R mediated G-protein activation is selectively influenced by SGIP1, β-arrestin associated signaling is changed profoundly, most likely as a consequence of the prevention of the receptor's internalization elicited by SGIP1.

• MeSH
• beta arrestin 2 metabolismus   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• endocytóza účinky léků   fyziologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• MAP kinasový signální systém fyziologie   MeSH
• mozek metabolismus   MeSH
• myši MeSH
• neurony metabolismus   MeSH
• potkani Wistar MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• Saccharomyces cerevisiae MeSH
• techniky dvojhybridového systému MeSH
• transfekce MeSH
• transportní proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• agonisté kanabinoidních receptorů farmakologie   MeSH
• antagonisté kanabinoidních receptorů farmakologie   terapeutické užití   MeSH
• endokanabinoidy * farmakologie   metabolismus   MeSH
• kanabinoidy farmakologie   škodlivé účinky   MeSH
• modely u zvířat MeSH
• modulátory kanabinoidních receptorů farmakologie   MeSH
• receptor kanabinoidní CB1 metabolismus   účinky léků   MeSH
• Publikační typ
• přehledy MeSH