Dissecting the Signaling Pathways Involved in the Crosstalk between Metabotropic Glutamate 5 and Cannabinoid Type 1 Receptors

Olmo, Isabella G.; Ferreira-Vieira, Talita H.; Ribeiro, Fabíola M.

doi:10.1124/mol.116.104372

Cited by 22 publications

(25 citation statements)

References 160 publications

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“…The mGlu 5 /CB 1 signalosome complex might play a major role in nociception. 40 The literature has very little to say about the link between the ECs and glutamatergic pathways in the periphery and the importance of the relationship between circulating levels of mediators of the EC systems and glutamate. To the best of our knowledge, this is the first study to report about the relationship of circulating anandamide and glutamate levels in chronic pain patients and HC before and after a physical exercise intervention.…”

Section: Discussionmentioning

confidence: 99%

Altered relationship between anandamide and glutamate in circulation after 30 min of arm cycling: A comparison of chronic pain subject with healthy controls

Stensson

Grimby-Ekman²

2019

Mol Pain

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The insufficient knowledge of biochemical mechanisms behind the emergence and maintenance of chronic musculoskeletal pain conditions constrains the development of diagnostic and therapeutic tools for clinical use. However, physical activity and exercise may improve pain severity and physical function during chronic pain conditions. Nevertheless, the biochemical consequences of physical activity and exercise in chronic pain need to be elucidated to increase the precision of this therapeutic tool in chronic pain treatment. The endocannabinoid system has been suggested to play an important role in exercise-induced reward and pain inhibition. Moreover, glutamatergic signalling has been suggested as an important factor for sensation and transmission of pain. In addition, a link has been established between the endocannabinoid system and glutamatergic pathways. This study examines the effect of dynamic load arm cycling (30 min) on levels of lipid mediators related to the endocannabinoid system and glutamate in plasma of chronic pain subjects and pain-free controls. Pain assessments and plasma levels of arachidonoylethanolamide (anandamide), 2-aracidonoylglycerol, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide and glutamate from 21 subjects with chronic neck pain (chronic pain group) and 11 healthy controls were analysed pre and post intervention of dynamic load arm cycling. Pain intensity was significantly different between groups pre and post exercise. Post exercise, anandamide levels were significantly decreased in health controls but not in the chronic pain group. A strong positive correlation existed between anandamide and glutamate in the control group post exercise but not in the chronic pain group. Moreover, the glutamate/anandamide ratio increased significantly in the control group and differed significantly with the chronic pain group post exercise. The altered relationship between anandamide and glutamate after the intervention in the chronic pain group might reflect alterations in the endocannabinoid-glutamate mechanistic links in the chronic pain group compared to the painfree control group.

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Section: Discussionmentioning

confidence: 99%

Altered relationship between anandamide and glutamate in circulation after 30 min of arm cycling: A comparison of chronic pain subject with healthy controls

Stensson

Grimby-Ekman²

2019

Mol Pain

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“…Furthermore, this increased mGluR5 availability positively correlated with avoidance symptom severity in the PTSD group 20 . Another PET study revealed increased endocannabinoid receptor type 1 (CB1) availability associated with PTSD 22 , which is interesting because CB1 receptors are inhibitory presynaptic receptors that are functionally linked to post-synaptic mGluR5 signaling 23 .…”

Section: The American Psychiatricmentioning

confidence: 99%

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

Tyler

Weinberg

Lovelock

et al. 2020

Preprint

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Persistent changes in brain stress and glutamatergic function are associated with post-traumatic stress disorder (PTSD). Rodent exposure to the predator odor trimethylthiazoline (TMT) is an innate stressor that produces lasting behavioral consequences relevant to PTSD. As such, the goal of the present study was to assess early (6 hours and 2 days) and late (4 weeks) changes to gene expression (RT-PCR) related to stress and excitatory function following TMT exposure in male, Long-Evans rats. During TMT exposure, rats engaged in stress reactive behaviors, including digging and immobility. Further, the TMT group displayed enhanced exploration and mobility in the TMT-paired context one week after exposure, suggesting a lasting contextual reactivity. Gene expression analyses revealed upregulated FKBP5 6 hours post-TMT in the hypothalamus and dorsal hippocampus. Two days after TMT, GRM3 was downregulated in the prelimbic cortex and dorsal hippocampus, but upregulated in the nucleus accumbens. This may reflect an early stress response (FKBP5) that resulted in later glutamatergic adaptation (GRM3).Finally, four weeks after TMT exposure, several differentially expressed genes known to mediate excitatory tripartite synaptic function were observed. Specifically in the prelimbic cortex (GRM5, DLG4 and SLC1A3 upregulated), infralimbic cortex (GRM2 downregulated, Homer1 upregulated), nucleus accumbens (GRM7 and SLC1A3 downregulated), dorsal hippocampus (FKBP5 and NR3C2 upregulated, SHANK3 downregulated) and ventral hippocampus (CNR1, GRM7, GRM5, SHANK3, and Homer1 downregulated). These data demonstrate that TMT exposure stress induces early and late stress and excitatory molecular adaptations, which may help us understand the persistent glutamatergic dysfunction observed in PTSD.

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“…Indeed, in excitatory synapses, mGlu 5 Rs, that are typically located peri-synaptically, are activated by glutamate (Glut) "spill over" occurring during hyper-excitable states (like epileptic seizures), so producing a feed-forward mechanism. 16 After Glut binding, mGlu 5 Rs (coupled with G q/11 proteins) activate phospholipase C β (PLCβ), which catalyzes the synthesis of diacylglycerol (DAG), a second messenger and precursor of 2-AG. When high levels of DAG are available, the enzyme diacylglycerol lipase α (DGLα) converts DAG into 2-AG, which migrates in a retrograde way to the presynaptic membrane.…”

Section: Phytocannabinoids and Endocannabinoids: A Brief Overviewmentioning

confidence: 99%

“…When high levels of DAG are available, the enzyme diacylglycerol lipase α (DGLα) converts DAG into 2-AG, which migrates in a retrograde way to the presynaptic membrane. 16,17 Interestingly, mGlu 5 Rs, PLCβ and DGLα are all anchored together and structurally organized by HOMER, a scaffold protein, forming a supramolecular complex called "2-AG signalome". 16 When 2-AG binds pre-synaptic CB 1 (coupled with G i/o ), its activation triggers various molecular pathways, including the inhibition of adenylate cyclase and of voltage-gated calcium channels (VGCC), which determines the decrease of Ca 2+ intracellular levels at the presynaptic terminal, resulting in neurotransmitter (Glut) release reduction.…”

Section: Phytocannabinoids and Endocannabinoids: A Brief Overviewmentioning

confidence: 99%

<p>Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects</p>

Morano¹,

Fanella²,

Albini³

et al. 2020

NDT

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Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ 9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB 1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT 1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fatcontaining meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies' approval was granted based on four pivotal double-blind, placebocontrolled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.

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Dissecting the Signaling Pathways Involved in the Crosstalk between Metabotropic Glutamate 5 and Cannabinoid Type 1 Receptors

Cited by 22 publications

References 160 publications

Altered relationship between anandamide and glutamate in circulation after 30 min of arm cycling: A comparison of chronic pain subject with healthy controls

Altered relationship between anandamide and glutamate in circulation after 30 min of arm cycling: A comparison of chronic pain subject with healthy controls

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

<p>Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects</p>

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