Evaluation of protective effects of non-selective cannabinoid receptor agonist WIN 55,212-2 against the nitroglycerine-induced acute and chronic animal models of migraine: A mechanistic study

Vosough, Elahe Mohammadi; Rahimi, Vafa Baradaran; Masoud, Seyyed Ali; Mirkarimi, Hamid Reza; Demneh, Maryam Kazemi; Abed, Alireza; Banafshe, Hamid Reza; Askari, Vahid Reza

doi:10.1016/j.lfs.2019.116670

Cited by 12 publications

(11 citation statements)

References 51 publications

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“…Our findings are in line with the result of that study, although we used a different cannabinoid agonist mAEA. However, in the same study, it was shown that WIN 55,212‐2 also reduced NTG‐induced hyperalgesia via both CB1 and CB2 receptors in chronic model of migraine induced by NTG (Mohammadi Vosough et al, 2019). But differently from that study, in current study, we used acute model of migraine induced by NTG, and targeted neuroinflammatory neuropeptides and immune mast cells in the strategical structures related to migraine.…”

Section: Discussionmentioning

confidence: 92%

“…There may be two possible explanations of this: (a) activation of TRPV1 receptors results in high Ca 2+ influx into neurons, and exocytosis of CGRP from the axon terminal is triggered by such an increase in the cytosolic calcium concentrations, and (b) desensitization of TRPV1 receptors due to prolonged or high‐dose exposure to mAEA which is metabolically more stable than endogenous anandamide. Moreover, a recent study showed that non‐selective cannabinoid receptor agonist WIN55,212‐2 alleviated the level of pain via CB1 but not CB2 receptor in acute model of migraine induced by NTG in rats (Mohammadi Vosough et al, 2019). Our findings are in line with the result of that study, although we used a different cannabinoid agonist mAEA.…”

Section: Discussionmentioning

confidence: 99%

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Receptor mechanisms mediating the anti‐neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine

Kılınç

Ankarali

Torun

et al. 2020

Eur J of Neuroscience

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Calcitonin gene-related peptide (CGRP), substance P and dural mast cells are main contributors in neurogenic inflammation underlying migraine pathophysiology. Modulation of endocannabinoid system attenuates migraine pain, but its mechanisms of action remain unclear. We investigated receptor mechanisms mediating anti-neuroinflammatory effects of endocannabinoid system modulation in in vivo migraine model and ex vivo hemiskull preparations in rats. To induce acute model of migraine, a single dose of nitroglycerin was intraperitoneally administered to male rats. Moreover, isolated ex vivo rat hemiskulls were prepared to study CGRP and substance P release from meningeal trigeminal afferents. We used methanandamide (cannabinoid agonist), rimonabant (cannabinoid receptor-1 CB1 antagonist), SR144528 (CB2 antagonist) and capsazepine (transient receptor potential vanilloid-1 TRPV1 antagonist) to explore effects of endocannabinoid system modulation on the neurogenic inflammation, and possible involvement of CB1, CB2 and TRPV1 receptors during endocannabinoid effects. Methanandamide attenuated nitroglycerin-induced CGRP increments in in vivo plasma, trigeminal ganglia and brainstem and also in ex vivo hemiskull preparations. Methanandamide also alleviated enhanced number and degranulation of dural mast cells induced by nitroglycerin. Rimonabant, but not capsazepine or SR144528, reversed the attenuating effects of methanandamide on CGRP release in both in vivo and ex vivo experiments. Additionally, SR144528, but not rimonabant or capsazepine, reversed the attenuating effects of methanandamide on dural mast cells. However, neither nitroglycerin nor methanandamide changed substance P levels in both in vivo and ex vivo experiments. Methanandamide modulates CGRP release in migraine-related structures via CB1 receptors and inhibits the degranulation of dural mast cells through CB2 receptors. Selective ligands targeting CB1 and CB2 receptors may provide novel and effective treatment strategies against migraine.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Receptor mechanisms mediating the anti‐neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine

Kılınç

Ankarali

Torun

et al. 2020

Eur J of Neuroscience

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“…To antagonize CB1 and CB2 receptors, we used AM251 ((N-(piperidin-1-yl)-5-(4iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide)) and AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl](4-methoxyphenyl)), respectively. Both antago-nists were dissolved in the same JZL15 vehicle (2 mL/kg) and were administered at a dose of 1 mg/kg, i.p [35].…”

Section: Drugs and Treatmentmentioning

confidence: 99%

Dual Inhibition of FAAH and MAGL Counteracts Migraine-like Pain and Behavior in an Animal Model of Migraine

Greco¹,

Demartini²,

Francavilla³

et al. 2021

Cells

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The endocannabinoid system exerts an important role in pain processing and modulation. Modulation of the system with hydrolase inhibitors of anandamide (AEA) or 2-arachidonyl glycerol (2-AG) has proved effective in reducing migraine-like features in animal models of migraine. Here, we investigated the effect of dual inhibition of the AEA and 2-AG catabolic pathways in the nitroglycerin-based animal model of migraine. The dual inhibitor JZL195 was administered to rats 2 h after nitroglycerin or vehicle injection. Rats were then exposed to the open field test and the orofacial formalin test. At the end of the tests, they were sacrificed to evaluate calcitonin gene-related peptide (CGRP) serum levels and gene expression of CGRP and cytokines in the cervical spinal cord and the trigeminal ganglion. The dual inhibitor significantly reduced the nitroglycerin-induced trigeminal hyperalgesia and pain-associated behavior, possibly via cannabinoid 1 receptors-mediated action, but it did not change the hypomotility and the anxiety behaviors induced by nitroglycerin. The decreased hyperalgesia was associated with a reduction in CGRP and cytokine gene expression levels in central and peripheral structures and reduced CGRP serum levels. These data suggest an antinociceptive synergy of the endocannabinoid action in peripheral and central sites, confirming that this system participates in reduction of cephalic pain signals.

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“…Several classes of compounds acting as CB2R agonists have been developed in the past years, bearing different scaffolds: dibenzopyran, , oxoquinoline, − naphthyridinone, − quinolinedione alkyloxy-coumarin indole, − indazole imidazopyridine, imidazopyrazine, benzimidazole, , purine, , thiophene, , triazine, , pyridinone, − biphenyl, , proline, , and piperidine . In Figure the most representative and selective known CB2R ligands are reported along with their K i values on CB1R and CB2R.…”

Section: Cb2r Agonists: the Proposed Pharmacophorementioning

confidence: 99%

“…The presence of OH or CO groups in the 2- or 4-position of the core increases the affinity vs the target via H-bonds formation . On the core scaffold, R 1 can be (i) a linear alkyl chain (four to six carbon atoms) often formed by five methylene units (that proved to be optimal for receptor affinity − due to their ability to maximize the interactions with a hydrophobic region of the receptor), (ii) cycloalkyl or aromatic alkyl groups, (iii) heterocycloalkyl ring such as alkylmorpholine or piperidine …”

Section: Cb2r Agonists: the Proposed Pharmacophorementioning

confidence: 99%

Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

et al. 2020

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The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression. Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders. With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders. Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.

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Evaluation of protective effects of non-selective cannabinoid receptor agonist WIN 55,212-2 against the nitroglycerine-induced acute and chronic animal models of migraine: A mechanistic study

Cited by 12 publications

References 51 publications

Receptor mechanisms mediating the anti‐neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine

Receptor mechanisms mediating the anti‐neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine

Dual Inhibition of FAAH and MAGL Counteracts Migraine-like Pain and Behavior in an Animal Model of Migraine

Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

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