Alterations in the excitability of dorsal root ganglion (DRG) neurons are critical in the pathogenesis of acute and chronic pain. Neurotransmitter release from the terminals of DRG neurons is regulated by cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both activated by anandamide (AEA). In our experiments, the AEA precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE) was used to study the modulation of nociceptive DRG neurons excitability using K+-evoked Ca2+ transients. Intrathecal administration was used to evaluate in vivo effects. Application of 20:4-NAPE at lower concentrations (10 nM - 1 μM) decreased the excitability of DRG neurons, whereas the higher (10 μM) increased it. Both effects of 20:4-NAPE were blocked by the N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. Similarly, lower concentrations of externally applied AEA (1 nM - 10 nM) inhibited DRG neurons, whereas higher concentration (100 nM) did not change it. High AEA concentration (10 μM) evoked Ca2+ transients dependent on TRPV1 activation in separate experiments. Inhibition of the CB1 receptor by PF514273 (400 nM) prevented the 20:4-NAPE- and AEA-induced inhibition, whereas TRPV1 inhibition by SB366791 (1 μM) prevented the increased DRG neuron excitability. In behavioral tests, lower 20:4-NAPE concentration caused hyposensitivity, while higher evoked mechanical allodynia. Intrathecal LEI-401 prevented both in vivo effects of 20:4-NAPE. These results highlight anti- and pro-nociceptive effects of 20:4-NAPE mediated by CB1 and TRPV1 in concentration-dependent manner. Our study underscores the complexity of endocannabinoid signaling in pain transmission modulation and highlights 20:4-NAPE as a potential therapeutic target, offering new insights for developing analgesic strategies.

• MeSH
• endokanabinoidy farmakologie   metabolismus   MeSH
• fosfatidylethanolaminy * farmakologie   MeSH
• fosfolipasa D * metabolismus   antagonisté a inhibitory   MeSH
• kationtové kanály TRPV metabolismus   MeSH
• krysa rodu rattus MeSH
• kyseliny arachidonové * farmakologie   MeSH
• neurony * účinky léků   metabolismus   MeSH
• polynenasycené alkamidy farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• spinální ganglia * účinky léků   metabolismus   cytologie   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Konopí seté (Cannabis sativa) je rostlina, která byla do 19. století v Čechách i na Moravě zdrojem suroviny pro výrobu textilního materiálu kanafasu. S rozvojem výzkumu endokanabinoidního systému se tato rostlina dostává opět do popředí zájmu. Endokanabinoidní systém ovlivňuje homeostázu celého organismu na bázi modulace aktivity jiných neurotransmiterů, např. nocicepci, kognici, spasticitu, spánek aj. Kanabinoidní receptory se nachází v periferním (CB2) i centrálním nervovém systému (CB1), ale i v pojivových tkáních a imunitním systému. Nejznámějšími účinnými molekulami je delta-9-tetrahydrokanabinol (THC) a kanabidiol (CBD). Prezentuji kazuistiku pacienta s chronickými vertebrogenními obtížemi a polyneuropatií dolních končetin doprovázenou neuropatickou bolestí. Léčebné konopí v monoterapii nebo kombinované terapii může být dobrou volbou pro pacienty při léčbě neuropatické bolesti v individualizované léčbě.

Hemp (Cannabis sativa) is a herb which was used for the production of canvas until the 19th century in Bohemia and Moravia. The progress in research focused on endocanabinoid system brings this herb into the focus again. Endocanabinoid system influences homeostasis of the whole organism due to modulation of neurotransmiter activity and subsequently the nociception, cognition, spasticity, sleep etc. Cannabinoid receptors are situated in the peripheral (CB2) and central nervous system (CB1), as well as in the connective tissue and immune system. The best-known effective molecules are delta-9-tetrahydrocanabinol (THC) and cannabidiol (CBD). I present a case report of a patient with chronic vertebrogenic problems and polyneuropathy of the lower extremities accompanied by neuropathic pain. Medical cannabis in monotherapy or in combination therapy can be a good choice for patients with neuropathic pain in individualized treatment.

• MeSH
• Cannabis * MeSH
• endokanabinoidy farmakologie   terapeutické užití   MeSH
• kanabidiol metabolismus   terapeutické užití   MeSH
• kazuistiky jako téma MeSH
• lidé MeSH
• marihuana pro léčebné účely * farmakologie   terapeutické užití   MeSH
• neuralgie diagnóza   farmakoterapie   MeSH
• receptory kanabinoidní MeSH
• tetrahydrokanabinol metabolismus   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• přehledy 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

Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100 Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5 mg/kg, twice daily for 7 days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3 mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.

• MeSH
• amidohydrolasy * antagonisté a inhibitory   metabolismus   MeSH
• antagonisté excitačních aminokyselin farmakologie   aplikace a dávkování   MeSH
• benzamidy * farmakologie   MeSH
• endokanabinoidy metabolismus   MeSH
• fencyklidin * farmakologie   MeSH
• gama rytmus EEG fyziologie   účinky léků   MeSH
• karbamáty * farmakologie   MeSH
• krysa rodu rattus MeSH
• kyseliny arachidonové metabolismus   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny * farmakologie   MeSH
• polynenasycené alkamidy metabolismus   farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra účinky léků   metabolismus   patofyziologie   MeSH
• pyrazoly farmakologie   MeSH
• schizofrenie * patofyziologie   metabolismus   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB1) and Transient receptor potential vanilloid (TRPV1) receptors. The role of AEA (1 μM, 10 μM, and 30 μM) application on the modulation of nociceptive synaptic transmission under control and inflammatory conditions was studied by recording miniature excitatory postsynaptic currents (mEPSCs) from neurons in spinal cord slices. Inhibition of the CB1 receptors by PF514273, TRPV1 by SB366791, and the fatty acid amide hydrolase (FAAH) by URB597 was used. Under naïve conditions, the AEA application did not affect the mEPSCs frequency (1.43±0.12 Hz) when all the recorded neurons were considered. The mEPSC frequency increased (180.0±39.2%) only when AEA (30 μM) was applied with PF514273 and URB597. Analysis showed that one sub-population of neurons had synaptic input inhibited (39.1% of neurons), the second excited (43.5%), whereas 8.7% showed a mixed effect and 8.7% did not respond to the AEA. With inflammation, the AEA effect was highly inhibitory (72.7%), while the excitation was negligible (9.1%), and 18.2% were not modulated. After inflammation, more neurons (45.0%) responded even to low AEA by mEPSC frequency increase with PF514273/URB597 present. AEA-induced dual (excitatory/inhibitory) effects at the 1st nociceptive synapse should be considered when developing analgesics targeting the endocannabinoid system. These findings contrast the clear inhibitory effects of the AEA precursor 20:4-NAPE application described previously and suggest that modulation of endogenous AEA production may be more favorable for analgesic treatments.

• MeSH
• amidohydrolasy MeSH
• analgetika farmakologie   MeSH
• benzamidy * MeSH
• endokanabinoidy * farmakologie   MeSH
• karbamáty * MeSH
• kyseliny arachidonové * MeSH
• lidé MeSH
• nocicepce * MeSH
• polynenasycené alkamidy farmakologie   MeSH
• zadní rohy míšní MeSH
• zánět farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Kanabinoidy, aktivní složky rostliny Cannabis, ovlivňují širokou škálu fyziologických procesů prostřednictvím endokanabinoidního systému, který zahrnuje receptory CB1 a CB2, endogenní ligandy a regulační enzymy. Tento přehledový článek shrnuje mechanismy působení fytokanabinoidů, syntetických kanabinoidů a endokanabi noidů, včetně jejich farmakologických vlastností, terapeutického potenciálu a rizik spojených s jejich použitím. Diskutována je také toxicita syntetických kanabinoidů, jejichž rekreační užívání představuje významnou hrozbu pro veřejné zdraví. Závěrem jsou uvedeny současné aplikace kanabinoidů v klinické praxi, zejména při léčbě bolesti, nevolnosti a neurologických onemocnění.

Cannabinoids, active compounds of the Cannabis plant, influence a wide range of physiological processes through the endocannabinoid system, comprising CB1 a CB2 receptors, endogenous ligands, and regulatory enzymes. This review summarizes the mechanisms of action of phytocannabinoids, synthetic cannabinoids, and endo­cannabinoids, including their pharmacological properties, therapeutic potential, and associated risks. The article also discusses the toxicity of synthetic cannabinoids, highlighting the public health threat posed by their recreational use. Finally, it explores current clinical applications of cannabinoids, particularly in the treatment of pain, nausea, and neurological disorders.

• Klíčová slova
• syntetické kanabinoidy,
• MeSH
• endokanabinoidy farmakologie   terapeutické užití   MeSH
• kanabinoidy farmakologie   terapeutické užití   MeSH
• lidé MeSH
• marihuana pro léčebné účely * farmakologie   terapeutické užití   MeSH
• receptor kanabinoidní CB1 MeSH
• receptor kanabinoidní CB2 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Cannabinoid CB1 receptors have been shown to regulate wide array of functions ranging from homeostasis to the cognitive functioning but recent data support the hypothesis that astrocytes also operate as a mediator of synaptic plasticity and contribute to cognition and learning. The receptor heterogeneity plays a key role in understanding the molecular mechanisms underlying these processes. Despite the fact that the majority of CB1 receptors act on neurons, studies have revealed that cannabinoids have direct control over astrocytes, including energy generation and neuroprotection. The tripartite synapse connects astrocytes to neurons and allows them to interact with one another and the astrocytes are key players in synaptic plasticity, which is associated with cognitive functions. This review focuses on our growing understanding of the intricate functions of astroglial CB1 that underpin physiological brain function, and in Alzheimer's disease.

• MeSH
• Alzheimerova nemoc * MeSH
• astrocyty MeSH
• endokanabinoidy MeSH
• kognitivní dysfunkce * MeSH
• lidé MeSH
• neurony MeSH
• neuroplasticita fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• chronická bolest * MeSH
• endokanabinoidy fyziologie   MeSH
• kanabidiol farmakologie   terapeutické užití   MeSH
• léky na předpis MeSH
• lidé středního věku MeSH
• lidé MeSH
• marihuana pro léčebné účely * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• receptor kanabinoidní CB1 fyziologie   MeSH
• receptor kanabinoidní CB2 fyziologie   MeSH
• tetrahydrokanabinol aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Autaptic hippocampal neurons are an architecturally simple model of neurotransmission that express several forms of cannabinoid signaling. Over the past twenty years this model has proven valuable for studies ranging from enzymatic control of endocannabinoid production and breakdown, to CB1 receptor structure/function, to CB2 signaling, understanding 'spice' (synthetic cannabinoid) pharmacology, and more. However, while studying cannabinoid signaling in these neurons, we have occasionally encountered what one might call 'interesting negatives', valid and informative findings in the context of our experimental design that, given the nature of scientific publishing, may not otherwise find their way into the scientific literature. In autaptic hippocampal neurons we have found that: (1) The fatty acid binding protein (FABP) blocker SBFI-26 does not alter CB1-mediated neuroplasticity. (2) 1-AG signals poorly relative to 2-AG in autaptic neurons. (3) Indomethacin is not a CB1 PAM in autaptic neurons. (4) The CB1-associated protein SGIP1a is not necessary for CB1 desensitization. We are presenting these negative or perplexing findings in the hope that they will prove beneficial to other laboratories and elicit fruitful discussions regarding their relevance and significance.

• MeSH
• endokanabinoidy MeSH
• hipokampus MeSH
• kanabinoidy * farmakologie   MeSH
• nervový přenos MeSH
• neurony MeSH
• Publikační typ
• časopisecké články MeSH

Vzhledem k nedávným legislativním změnám je v současné době opět možné používat konopí pro léčebné účely, přičemž zájem o tento způsob léčby velmi narůstá. Tento přehledový článek popisuje stručnou historii využívání konopí a základní klasifikaci jeho obsahových látek. Zaměřuje se na farmakodynamiku a farmakokinetiku hlavních kanabinoidů THC a CBD včetně definice a významu endokanabinoidního systému. V textu jsou zmíněny v praxi používané aplikační způsoby a lékové formy. Dále text stručně shrnuje specializované způsobnosti lékařů, kteří mohou konopí předepsat, a hlavní indikace, nežádoucí účinky a kontraindikace související s léčebným využitím konopí, i s ohledem na bezpečnost řízení motorových vozidel. Poslední část tohoto přehledového článku je zaměřena na terapii bolesti a pro ilustraci jsou uvedeny dvě případové studie skutečných pacientů léčených konopím.

Since the recent changes in legislation, it is presently possible to use cannabis for medical purposes and there is an increasing interest in this mode of treatment. This review describes brief history of cannabis use and basic classification of substances found in the plant. It is focused on pharmacodynamics and pharmacokinetics of the main cannabinoids THC and CBD, with note on definition and significance of endocannabinoid system. Practically used routes of administration and drug dosage forms are mentioned as well. Furthermore, the article concisely summarizes specializations of physicians, who can prescribe medical cannabis, its main indications, adverse effects and contraindications, including aspect of safe driving in patients with this treatment. The last part of this review is aimed at therapy of pain and it brings two case reports of real patients treated with medical cannabis.

• MeSH
• bolest farmakoterapie   MeSH
• endokanabinoidy farmakologie   MeSH
• kanabidiol dějiny   farmakologie   MeSH
• kanabinoidy farmakologie   klasifikace   MeSH
• kontraindikace MeSH
• lékové formy MeSH
• lidé středního věku MeSH
• lidé MeSH
• marihuana pro léčebné účely * analýza   aplikace a dávkování   dějiny   farmakologie   MeSH
• migréna farmakoterapie   MeSH
• odborná způsobilost zákonodárství a právo   MeSH
• tetrahydrokanabinol farmakologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH