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Synaptic plasticity, defined as the modification of synaptic strength, plays a very important role in
many mechanisms such as memory or learning. There are several types of synaptic plasticity, the best known and most studied being homosynaptic plasticity where a synapse strength is modified by its own activity. However, this type of plasticity cannot explain all phenomena and other types of plasticity are needed. Heterosynaptic plasticity is defined as changes in the synaptic strength induced by the activity of adjacent synapses. Until now, only scarce data, either experimental or computational, have been generated to study heterosynaptic plasticity. Yet, this type of plasticity is necessary, especially to study pain-related phenomena.
Pain may be triggered by various causes. Moreover, following an injury, one can notice an increase in sensitivity to touch on and around the wound. Thus, a caress, no matter how gentle, will cause a sensation of pain. This phenomenon is known as allodynia. Studies have shown that central sensitization, an increase in the excitation of synapses in the spinal cord, has a role to play in the induction of allodynia. Both homosynaptic and heterosynaptic plasticities are involved.
The aim of this thesis is to establish a new model of heterosynaptic plasticity with the subsidiary
goal of modeling allodynia. To do so, we started with two homosynaptic plasticity models (calcium-based and pair-based spike-timing dependent plasticity (STDP)) to which we added a heterosynaptic dimension by modeling two presynaptic neurons and one postsynaptic neuron. In the calcium-based model, this has been done through the integration of a new parameter α, intervening when presynaptic neurons spike, which could represent the distance between two presynaptic neurons or the amount of calcium diffusing (or being released) through the postsynaptic neuron. In the pair-based model, this has been done through the integration of two new parameters α, governing the potentiation, and Ahet governing the depression of synaptic weights. Both parameters intervene when the presynaptic neurons spike. We studied the dependency between α and Ahet which shows that when they are independent of each other, a phenomenon of pruning, the mechanism by which some neuronal connections are eliminated after some time, can be inferred with the right set of parameters. Our new calcium-based heterosynaptic models were evaluated in the same experimental conditions previously
reported by Chistiakova et al. and we were able to reproduce a Mexican hat pattern where the
induction of homosynaptic long-term potentiation (LTP) provokes weaker LTP at the closest neighbor
synapses, long-term depression (LTD) at further neighbor synapses and no modification at the furthest neighbor synapses. Finally, we were able to customize our new models to reproduce a mechanism of heterosynaptic central sensitization causing allodynia. However, our models have shown a certain fragility that may be related to suboptimal physiological modeling.
In conclusion, our new models introduced for the first time two new parameters namely α and Ahet which, in our view, could contribute to better model heterosynaptic plasticity. However, further work will be needed to flesh out our models in the future.

Heterosynaptic plasticity --- Allodynia --- Biological neuron model --- synaptic plasticity --- Ingénierie, informatique & technologie > Multidisciplinaire, généralités & autres

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During the last 60 years the relevance of cannabis (Cannabis sativa or Cannabis indica) ingredients, like the psychoactive Δ9-tetrahydrocannabinol (THC), cannabidiol, 120+ additional cannabinoids and 440+ non-cannabinoid compounds, for human health and disease has become apparent. Approximately 30 years after the elucidation of THC structure the molecular reasons for the biological activity of these plant extracts were made clearer by the discovery of endocannabinoids, that are endogenous lipids able to bind to the same receptors activated by THC. Besides endocannabinoids, that include several N-acylethanolamines and acylesters, a complex array of receptors, metabolic enzymes, transporters (transmembrane, intracellular and extracellular carriers) were also discovered, and altogether they form a so-called “endocannabinoid system” that has been shown to finely tune the manifold biological activities of these lipid signals. Both plant-derived cannabinoids and endocannabinoids were first discovered by the group led by Prof. Dr. Raphael Mechoulam, who has just celebrated his 90th birthday and clearly stood out as a giant of modern science. The many implications of his seminal work for chemistry, biochemistry, biology, pharmacology and medicine are described in this special issue by the scientists who reached during the last 20 years the highest recognition in the field of (endo)cannabinoid research, receiving the Mechoulam Award for their major contributions. I thank them for having accepted my invitation to be part of this honorary issue of Molecules, and Raphi for continuing to illuminate our field with his always inspiring investigations and new ideas.

Research & information: general --- Biology, life sciences --- Biochemistry --- cannabinoid --- MRI-1867 --- hybrid ligand --- CB1 receptor antagonist --- iNOS inhibitor --- rimonabant --- intracerebroventricular administration --- alcohol craving --- two-bottle paradigm --- drinking in the dark --- N-acyltransferase --- anandamide --- endocannabinoid --- phospholipase A2 --- cannabichromene --- cannabidiolic acid --- cannabidivarin --- cannabidivarinic acid --- phytocannabinoids --- tetrahydrocannabivarin --- 4′-fluoro-cannabidiol --- cannabinoid tetrad --- elevated plus maze --- catalepsy --- marble bury --- HUF-101 --- equilibrative nucleoside transporter --- CB1 --- biased signaling --- functional selectivity --- G-protein --- β-arrestin --- cannabigerol --- anti-inflammatory --- obesity --- cannabinoid receptor 2 (CB2R) --- microglia --- inflammaging --- memory --- lipofuscin --- aminoalkylindole --- allodynia --- antinociception --- cannabinoid receptor --- CP55940 --- JWH-018 --- K2 --- pravadoline --- spice --- WIN55212-2 --- type 1 cannabinoid receptor CB1 --- cholesterol --- hippocampus --- frontal cortex --- synaptosomes --- rescue model --- anti-CB1 antibody --- cannabinoids --- GPR55 receptors --- VCE-006.1 --- chromenopyrazole --- Parkinson’s disease --- 6-hydroxydopamine --- lipopolysaccharide --- amyotrophic lateral sclerosis --- mSOD1 mice --- TDP-43 transgenic mice --- PPARs --- gut microbiome --- intestine --- ghrelin --- LEAP2 --- n/a --- 4'-fluoro-cannabidiol --- Parkinson's disease

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Zinc-dependent matrix metalloproteinases (MMPs) belong to metzincins that comprise not only 23 human MMPs but also other metalloproteinases, such as 21 human ADAMs (a disintegrin and metalloproteinase domain) and 19 secreted ADAMTSs (a disintegrin and metalloproteinase thrombospondin domain). The many setbacks from the clinical trials of broad-spectrum MMP inhibitors for cancer indications in the late 1990s emphasized the extreme complexity of the participation of these proteolytic enzymes in biology. This editorial mini-review summarizes the Special Issue, which includes four review articles and 10 original articles that highlight the versatile roles of MMPs, ADAMs, and ADAMTSs, in normal physiology as well as in neoplastic and destructive processes in tissue. In addition, we briefly discuss the unambiguous involvement of MMPs in wound healing.

hemagglutinin-B --- transwell co-cultures --- matrix metalloproteinases --- TNF-α --- matrix metalloproteinase --- peritoneal mesothelial cell --- gastric cancer --- metastatic dissemination --- MT4-MMP --- cancer --- diseases --- aggrecan --- aggrecanase --- ADAMTS --- cartilage --- arthritis --- MMP-2 --- MMP-9 --- inhibitor --- allodynia --- caspase-3 --- neuropathic --- pain --- dorsal root ganglion --- spinal nerve ligation --- tuberculosis --- tuberculous meningitis --- HIV-TB-associated IRIS --- extracellular matrix breakdown --- adult --- pediatric --- lung --- central nervous system --- matrix-metalloproteinase --- monocytes --- inflammation --- phagocytosis --- apoptosis --- blood sampling --- anticoagulants --- high-molecular-weight heparin --- IL-16 --- sICAM-1 --- IL-8 --- T cells --- a disintegrin and metalloproteinase --- EMMPRIN --- CD147 --- ectodomain shedding --- MMPs --- PTMs --- glycosylation --- phosphorylation --- glycosaminoglycans --- interleukin --- IL-6 --- IL-11 --- trans-signaling --- metalloproteases --- ADAM --- MMP --- meprin --- matrix metalloproteinases (MMPs) --- protease --- signaling --- invasion --- chemokine --- cytokine --- proteomics --- interferon --- Agkistrodon venom --- metalloproteinase --- fibrinogen --- antithrombotic --- metabolomics --- extracellular matrix --- cytokines --- proteinases --- interstitial collagens --- wound healing

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Zinc-dependent matrix metalloproteinases (MMPs) belong to metzincins that comprise not only 23 human MMPs but also other metalloproteinases, such as 21 human ADAMs (a disintegrin and metalloproteinase domain) and 19 secreted ADAMTSs (a disintegrin and metalloproteinase thrombospondin domain). The many setbacks from the clinical trials of broad-spectrum MMP inhibitors for cancer indications in the late 1990s emphasized the extreme complexity of the participation of these proteolytic enzymes in biology. This editorial mini-review summarizes the Special Issue, which includes four review articles and 10 original articles that highlight the versatile roles of MMPs, ADAMs, and ADAMTSs, in normal physiology as well as in neoplastic and destructive processes in tissue. In addition, we briefly discuss the unambiguous involvement of MMPs in wound healing.

Research & information: general --- Biology, life sciences --- hemagglutinin-B --- transwell co-cultures --- matrix metalloproteinases --- TNF-α --- matrix metalloproteinase --- peritoneal mesothelial cell --- gastric cancer --- metastatic dissemination --- MT4-MMP --- cancer --- diseases --- aggrecan --- aggrecanase --- ADAMTS --- cartilage --- arthritis --- MMP-2 --- MMP-9 --- inhibitor --- allodynia --- caspase-3 --- neuropathic --- pain --- dorsal root ganglion --- spinal nerve ligation --- tuberculosis --- tuberculous meningitis --- HIV-TB-associated IRIS --- extracellular matrix breakdown --- adult --- pediatric --- lung --- central nervous system --- matrix-metalloproteinase --- monocytes --- inflammation --- phagocytosis --- apoptosis --- blood sampling --- anticoagulants --- high-molecular-weight heparin --- IL-16 --- sICAM-1 --- IL-8 --- T cells --- a disintegrin and metalloproteinase --- EMMPRIN --- CD147 --- ectodomain shedding --- MMPs --- PTMs --- glycosylation --- phosphorylation --- glycosaminoglycans --- interleukin --- IL-6 --- IL-11 --- trans-signaling --- metalloproteases --- ADAM --- MMP --- meprin --- matrix metalloproteinases (MMPs) --- protease --- signaling --- invasion --- chemokine --- cytokine --- proteomics --- interferon --- Agkistrodon venom --- metalloproteinase --- fibrinogen --- antithrombotic --- metabolomics --- extracellular matrix --- cytokines --- proteinases --- interstitial collagens --- wound healing

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The interest in opioids such as morphine, the prototypical opioid ligand, has been maintained through the years. The identification of endogenous opioids and their receptors (mu, delta, kappa, and nociceptin), molecular cloning, and the elucidation of the crystal structures of opioid receptors represent key milestones in opioid research. The opioid system modulates numerous pharmacological responses, with therapeutic (i.e., analgesia) and detrimental side effects (i.e., addiction). The medical use and misuse of opioids have dramatically increased, leading to the 21st century opioid crisis. This book presents recent developments in opioid drug discovery, specifically in the medicinal chemistry and pharmacology of new ligands targeting the opioid receptors as effective and safe therapeutics for human diseases. Furthermore, it draws a special attention to advancing concepts and strategies in opioid drug discovery to mitigate opioid liabilities. The diversity among the discussed topics is a testimony to the complexity of the opioid system, which results from the expression, regulation, and functional role of ligands and receptors. The array of multidisciplinary research areas illustrates the rapidly developing basic research and translational activities in opioid drug discovery. This book will serve as a useful reference while also stimulating continued research in the chemistry and pharmacology of opioids and their receptors, with the prospect of developing improved therapies for human diseases, but also improving health and quality of life in general.

opioid receptors --- neurokinin-1 receptor --- peptide synthesis --- receptor binding studies --- functional assay --- writhing test --- tolerance --- Leu-enkephalin --- beta-arrestin --- mu opioid receptor --- delta opioid receptor --- biased signaling --- DADLE --- ischemia --- plasma stability --- morphinan --- BNTX --- δ opioid receptor antagonist --- 1H-NMR experiments --- mechanism elucidation --- peripheral antinociception --- 14-methoxycodeine-6-O-sulfate --- codeine-6-O-sulfate --- opioid peptides and peptidomimetics --- DAMGO --- DALDA --- [Dmt1]DALDA --- KGOP01 --- binding --- molecular docking --- structure-activity relationships --- β2-amino acids --- β2-Homo-amino acids --- µ-opioid receptor --- opioid peptides --- TAPP --- racemic synthesis of β2-amino acids --- peripheral µ-opioid receptors --- analgesia --- peripheral analgesic tolerance --- dysbiosis --- opioid --- bifunctional ligands --- (−)-N-phenethylnorhydromorphone analogs --- [35S]GTPgammaS assay --- forskolin-induced cAMP accumulation assays --- β-arrestin recruitment assays --- MOR and DOR agonists --- respiratory depression --- bias factor --- molecular modeling &amp --- simulation --- δ opioid receptor --- NTI derivative --- sulfonamide --- inverse agonist --- neutral antagonist --- agonist --- opioids --- mu receptor --- opioid side effects --- biased agonism --- partial agonism --- zerumbone --- chronic constriction injury (CCI) --- allodynia --- hyperalgesia --- potassium channels --- over-the-counter drugs --- misuse --- abuse --- opioid drugs --- pharmacology --- codeine --- dihydrocodeine --- loperamide --- opioid peptide --- macrocyclic tetrapeptide --- multifunctional ligands --- kappa opioid receptor --- analgesics --- opioid liabilities --- μ opioid receptor --- receptor model --- biased ligands --- dependence --- pain therapy --- neonatal opioid withdrawal syndrome --- naltrexone --- 6β-naltrexol --- buprenorphine --- G-protein bias --- arrestin recruitment --- respiration --- mitragynine --- heteromer --- internalization --- primary hippocampal culture --- lysosomes --- µ opioid receptor --- molecular dynamics --- docking --- interaction fingerprints --- biased agonists --- SR-17018 --- PZM21 --- morphine --- fentanyl --- diphenethylamines --- design and synthesis --- structure–activity relationships --- partial agonist --- biased agonist --- antagonist --- binding affinity --- selectivity --- n/a