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The importance of the trigeminovascular system TGVS in migraine pathophysiology is widely recognized by experts in the field. Furthermore, the resulting sensitization has been found to stimulate TGVS activity, creating a positive feedback loop Eroli et al. The main migraine mediator associated with the TGVS system is the neuropeptide calcitonin gene-related peptide CGRP , which promotes vasodilation and contributes to the sterile meningeal inflammation associated with sensitization of nociceptive pathway Giniatullin et al.
Several papers from P. In particular serotonin, a major component of mast cell granules, is able to produce a robust activation of trigeminal afferents in meninges Kilinc et al. Both within CNS and peripherally, eCBs act as retrograde messengers or synaptic modulators for their respective target cells Gabral et al.
Unlike the selective presynaptic inhibitory effect of adenosine on excitatory glutamatergic terminals Safiulina et al.
CB2 receptor, being, like CB1 receptor, highly sensitive to 2-AG, possesses an individual set of expression patterns and characteristic functions. Endocannabinoid system contributes to both innate and adaptive immune responses, functioning as a preventative force against the onset of pro-inflammatory responses Nagarkatti et al.
CB2 receptors are primarily responsible for exerting immunosuppressive effects in the periphery. During an inflammatory reaction, which is expected in most severe or chronic forms of migraine, more of CB2 receptors are made available for activation Gabral et al.
In our recent study, familial migraine was found to be associated with enhanced concentrations of key inflammatory cytokines detected in blood Khaiboullina et al. Thus, cannabinoids may act by correcting the dysregulation of cytokine production Nagarkatti et al.
Taken together, these studies suggest that the less explored CB2 receptors possessing the anti-inflammatory potential Gabral et al. Besides their independent functions, CB1 and CB2 receptors have been shown to work together by forming hetero-receptor complexes Callen et al. This type of receptor-receptor interaction has been shown recently for brain-residing immune cells such as microglia. Thus, it has been recently shown that, alongside CB2 receptors, the CB1-CB2 heteroreceptor complexes are expressed in microglia Smith et al.
Microglia could play a part in the pathogenesis of migraine with aura, since the cortical spreading depression CSD associated with this type of migraine effectively activates microglia Shibata and Suzuki, Notably, the ability of microglia to secrete 2-AG is about times higher than that of astrocytes and neurons Walter et al. In view of the recent data, this link appears to be even more intriguing as microglia are essential for initiation of CSD Pusic et al.
Consistent with growing interest to the medications targeting receptor heteromers, a study using the bivalent CB1 antagonist specifically affecting dimerized CB1 receptors, showed pain-alleviating effects Zhang et al.
In peripheral migraine mechanisms, activation of TRPV1 receptor, a non-selective cation channel expressed in trigeminal nociceptors, leads to massive CGRP release Kageneck et al.
Our and other studies indicate an important contribution of TRPV1 receptors to migraine pathology Zakharov et al. This complexity may explain why increased doses of cannabinoids diminished their analgesic effect Kandasamy et al. It further creates an incentive for development of new synthetic CBs with minimal activity on TRPV1 receptors, or specific MAGL inhibitors, which, apart from triggering the accumulation of anti-nociceptive 2-AG, can decrease the level of the pro-nociceptive arachidonic acid AA and reduce pain Aaltonen et al.
Disruptions in supply or functionality of eCB ligands have been connected to numerous mental state disturbances and, particularly, to migraine. Migraine, along with comorbid conditions such as fibromyalgia and irritable bowel syndrome, share symptomatic commonalities of hyperalgesia as well as treatment resistance, likely stemming from common pathophysiological phenomenon: The lowered inhibitory activity of eCS in migraine, possibly due to reduced CB1 and CB2 receptor expression, serves as an assertion for the compensatory therapy with exogenous cannabinoids.
According to the CECD hypothesis, treatment of migraine using exogenous cannabinoids could be achieved with low doses due to predisposition for elevated neuronal excitability. The CECD-causing deficiencies can appear for congenital reasons, or can be acquired. There is a long history of using cannabinoids for effective treatment of pain conditions. Due to their long-standing status of out-lawed substances Baron, , it is worth taking a look at the arguments still standing in the way of legalization.
Overall, targeting ECS with peripherally acting drugs is a promising strategy for development of safe migraine treatments. However, there are still many insufficiently explored issues that may be detrimental for this seemingly harmless treatment.
Regularly experiencing chronic migraine pain can have adverse impacts on social relationships and job status which can lead into psychological distress Ramsden et al. In a study of the cannabis use for self-medication in Germany, Austria and Switzerland, Another group found that the self-treatment outcome was highly variable, with low doses tending to alleviate migraine while higher doses even triggering headaches Lu and Anderson, These findings call for creating a highly specific prescription for individual patients, which would be required for safe and successful treatment plan.
One of the main problems arising from the long-term usage of cannabis is the physical reliance on the pCBs, mainly THC. Moreover, there is evidence that patients can develop tolerance for pCBs Kandasamy et al. A crucial point when considering cannabinoid treatment is that smoking marijuana is the most common method of pCB self-administration.
When self-administering pCBs via smoking, the relief seekers often use marijuana mixed with tobacco leaves. In view of the recently established crosstalk between nicotinic cholinergic and ECS Scherma et al. Particularly interesting is the ability of the endogenous nicotinic antagonist kynurenic acid to counteract the addictive effects of CBs Justinova et al.
Notably, new derivatives of kynurenic acid were suggested recently as promising medicines for migraine Greco et al. Interestingly, the main migraine mediator CGRP can reduce the activity of nicotinic receptors Giniatullin et al. Cannabidiol CBD , the second most prevalent pCB, should also be explored in relation to migraine treatment.
This stands as an important milestone paving the way for possible repurposing of this CBD-based drug for treating migraine, as well as other related neurological conditions.
In summary, cannabinoids — due to their anticonvulsive, analgesic, antiemetic, and anti-inflammatory effects — present a promising class of compounds for both acute and prophylactic treatment of migraine pain. In view of the rapidly unfolding changes in the legal status of cannabis, research on endo cannabinoids has become pertinent once again.
Formal approval of a cannabinoid-based drug for other pathologies opens a possibility for repurposing these agents also to treat migraine. The abundance of CB1 receptors in the brain makes them an attractive target for treatment of migraine via blocking not only peripheral but also the central nociceptive traffic and reducing the pathologically enhanced cortical excitability predisposing to CSD.
CB2 receptors in immune cells can be targeted to reduce the inflammatory component associated with severe forms of migraine. Exogenous compounds lacking the unwanted peripheral pro-nociceptive component or eCBs generated via inhibited degradation pathways and combined with other supportive agents are most desirable for this aim. Moreover, primary stratification of patients to identify and predict the effectiveness of cannabinoid treatment can greatly improve the efficiency of this approach.
The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RG was supported by the Finnish Academy grant and by the program of competitive growth of Kazan Federal University and the subsidy 6. National Center for Biotechnology Information , U. Journal List Front Pharmacol v. Published online Apr Pinja Leimuranta 1 A. Leonard Khiroug 2 Neurotar Ltd.
Rashid Giniatullin 1 A. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. Received Jan 24; Accepted Apr The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Abstract In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Introduction Migraine is a debilitating disorder most commonly characterized by a unilateral hemicranial pulsating headache often accompanied by a great variety of other symptoms such as sensory disturbances and nausea Pavlovic et al.
Exogenous and Endogenous Agonists Endocannabinoid system ECS is a comprehensive signaling system present in virtually every cell type and playing a critical role in maintaining body homoeostasis Aizpurua-Olaizola et al. Open in a separate window. Peripheral The importance of the trigeminovascular system TGVS in migraine pathophysiology is widely recognized by experts in the field.
PRO and Contra of Cannabinoids in Migraine Treatment There is a long history of using cannabinoids for effective treatment of pain conditions. Conclusion In summary, cannabinoids — due to their anticonvulsive, analgesic, antiemetic, and anti-inflammatory effects — present a promising class of compounds for both acute and prophylactic treatment of migraine pain.
Targeting the endocannabinoid system: Cannabinoid CB1 receptor activation inhibits trigeminovascular neurons. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: Molecular targets of cannabidiol in neurological disorders. On the g-protein-coupled receptor heteromers and their allosteric receptor-receptor interactions in the central nervous system:
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(Cherney, ), leading to relief from migraine symptoms when CBD is used There are several methods of ingestion for CBD, each of which can be Vaping CBD oil can be an abortive measure if a headache is taking. The mechanism of action is less clear for CBD, which has been reported to . using it for migraine headache symptoms (Kandasamy et al., ). to alleviate migraine while higher doses even triggering headaches (Lu and Anderson, ). .. The role of the endocannabinoid system in eating disorders. So, theoretically, smoking cannabis and drinking alcohol may increase the effects of CBD. Those who take CBD daily to relieve symptoms of chronic illness and other This is no different than one's headache returning once the effects of.