Noncanonical Activity of Endocannabinoids and Their Receptors in Central and Peripheral Synapses

Балезина, О. П.; Tarasova, E. O.; Gaydukov, A. E.

doi:10.1134/s0006297921070038

Cited by 8 publications

(14 citation statements)

References 128 publications

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“…This is possible due to the interaction of the seven‐transmembrane domain receptor with different types of G‐proteins. In this regard, CB1 receptors were shown to associate not only with G i but also with both G s and G q proteins depending on the ligand interaction (Balezina et al., 2021; Diez‐Alarcia et al., 2016; Leo &Abood, 2021). We cannot rule out the possibility that in motor synapses, the activation of CB1 receptors by 2‐AG promotes the initiation of G q ‐related signaling involving PLC, DAG, and IP3.…”

Section: Discussionmentioning

confidence: 99%

“…The specific and peculiar role of ECs in neuromuscular junctions gains great attention (Balezina et al., 2021; Behl et al., 2022; Dalle et al., 2022; Ge et al., 2020; Morsch et al., 2018; Tarasova, Khotkina, Gaydukov, et al., 2021) but still remains poorly studied up to date. Despite the relatively low density of CB1 receptors on muscle membranes, their activation by ECs plays a significant role in muscle metabolism and homeostasis (Alger, 2013; Charytoniuk et al., 2022; Dalle et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

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Quantal size increase induced by the endocannabinoid 2‐arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses

Tarasova,

Bogacheva,

Chernyshev

et al. 2023

Synapse

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In mouse motor synapses, the exogenous application of the endocannabinoid (EC) 2‐arachidonoylglycerol (2‐AG) increases acetylcholine (ACh) quantal size due to the activation of CB1 receptors and the stimulation of ACh vesicular uptake. In the present study, microelectrode recordings of miniature endplate potentials (MEPP) revealed that this effect of 2‐AG is independent of brain‐derived neurotrophic factor (BDNF) signaling but involves the activation of calcitonin gene–related peptide (CGRP) receptors along with CB1 receptors. Potentiation of MEPP amplitude in the presence of 2‐AG was prevented by blockers of CGRP receptors and ryanodine receptors (RyR) and by inhibitors of phospholipase C (PLC) and Ca2+/calmodulin‐dependent protein kinase II (CaMKII). Therefore, we suggest a hypothetical chain of events, which starts from the activation of presynaptic CB1 receptors, involves PLC, RyR, and CaMKII, and results in CGRP release with the subsequent activation of presynaptic CGRP receptors. Activation of CGRP receptors is probably a part of a complex molecular cascade leading to the 2‐AG‐induced increase in ACh quantal size and MEPP amplitude. We propose that the same chain of events may also take place if 2‐AG is endogenously produced in mouse motor synapses, because the increase in MEPP amplitude that follows after prolonged tetanic muscle contractions (30 Hz, 2 min) was prevented by the blocking of CB1 receptors. This work may help to unveil the previously unknown aspects of the functional interaction between ECs and peptide modulators aimed at the regulation of quantal size and synaptic transmission.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quantal size increase induced by the endocannabinoid 2‐arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses

Tarasova,

Bogacheva,

Chernyshev

et al. 2023

Synapse

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“…Furthermore, DEGs observed in the present profiling specifically targeted neuropeptide signaling (npy, npy1r, nts, Sprr1a, and Slc6a4), retrograde endocannabinoid signaling, ion transport, and pain regulation pathways. Due to the deletion of CB1 on DRG neurons, its inhibitory effect on presynaptic neurotransmitter release is weakened ( Balezina et al, 2021 ), so the synthesis and release of presynaptic neurotransmitters increase, such as upregulation of npy, npy1r, and nts, which in turn causes the excitement of postsynaptic neurons and finally causes pain. Collectively, our results proved that the DEGs in the late phase of CB1 knockout correlated closely with neuropathic pain, which may provide new analgesic targets for neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

“…Our results showed that CB1 was absent on peripheral sensory neurons; the immune response and neuroinflammation caused by peripheral nerve injury were more serious. Due to the lack of presynaptic inhibition of CB1 ( Balezina et al, 2021 ; Patzke et al, 2021 ), peripheral nerve injury leads to glial overactivation and the release of a large amount of pain-causing substances and inflammatory mediators, which eventually causes exaggerated neuropathic pain, and the specific deep-level mechanism needs to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling in Mice With CB1 receptor Deletion in Primary Sensory Neurons Suggests New Analgesic Targets for Neuropathic Pain

Liu

Jia²,

et al. 2022

Front. Pharmacol.

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Type 1 and type 2 cannabinoid receptors (CB1 and CB2, respectively) mediate cannabinoid-induced analgesia. Loss of endogenous CB1 is associated with hyperalgesia. However, the downstream targets affected by ablation of CB1 in primary sensory neurons remain unknown. In the present study, we hypothesized that conditional knockout of CB1 in primary sensory neurons (CB1cKO) alters downstream gene expression in the dorsal root ganglion (DRG) and that targeting these pathways alleviates neuropathic pain. We found that CB1cKO in primary sensory neurons induced by tamoxifen in adult Advillin-Cre:CB1-floxed mice showed persistent hyperalgesia. Transcriptome/RNA sequencing analysis of the DRG indicated that differentially expressed genes were enriched in energy regulation and complement and coagulation cascades at the early phase of CB1cKO, whereas pain regulation and nerve conduction pathways were affected at the late phase of CB1cKO. Chronic constriction injury in mice induced neuropathic pain and changed transcriptome expression in the DRG of CB1cKO mice, and differentially expressed genes were mainly associated with inflammatory and immune-related pathways. Nerve injury caused a much larger increase in CB2 expression in the DRG in CB1cKO than in wildtype mice. Interfering with downstream target genes of CB1, such as antagonizing CB2, inhibited activation of astrocytes, reduced neuroinflammation, and alleviated neuropathic pain. Our results demonstrate that CB1 in primary sensory neurons functions as an endogenous analgesic mediator. CB2 expression is regulated by CB1 and may be targeted for the treatment of neuropathic pain.

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“…Anandamide and 2-arachidonylglycerol (2-AG) ( Figure 2 ), are lipid mediators derived mainly from arachidonic acid and are the most frequent biosynthetic routes [ 57 , 58 , 59 ]. Endocannabinoids, such as anandamide and its analogs, have been extensively studied as targets of new therapeutic options for disorders of the CNS, including the prevention of epileptic seizures [ 9 , 60 ].…”

Section: Endocannabinoids Plant Oils and Seizure Controlmentioning

confidence: 99%

The GABAergic System and Endocannabinoids in Epilepsy and Seizures: What Can We Expect from Plant Oils?

et al. 2022

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Seizures and epilepsy are some of the most common serious neurological disorders, with approximately 80% of patients living in developing/underdeveloped countries. However, about one in three patients do not respond to currently available pharmacological treatments, indicating the need for research into new anticonvulsant drugs (ACDs). The GABAergic system is the main inhibitory system of the brain and has a central role in seizures and the screening of new ACD candidates. It has been demonstrated that the action of agents on endocannabinoid receptors modulates the balance between excitatory and inhibitory neurotransmitters; however, studies on the anticonvulsant properties of endocannabinoids from plant oils are relatively scarce. The Amazon region is an important source of plant oils that can be used for the synthesis of new fatty acid amides, which are compounds analogous to endocannabinoids. The synthesis of such compounds represents an important approach for the development of new anticonvulsant therapies.

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Noncanonical Activity of Endocannabinoids and Their Receptors in Central and Peripheral Synapses

Cited by 8 publications

References 128 publications

Quantal size increase induced by the endocannabinoid 2‐arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses

Quantal size increase induced by the endocannabinoid 2‐arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses

Transcriptomic Profiling in Mice With CB1 receptor Deletion in Primary Sensory Neurons Suggests New Analgesic Targets for Neuropathic Pain

The GABAergic System and Endocannabinoids in Epilepsy and Seizures: What Can We Expect from Plant Oils?

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