Exp Neurol. Jul;(1) doi: /11motors-club.inforol Epub Mar The endocannabinoid system and migraine. Greco R(1), Gasperi. Front Neurosci. Mar 19; doi: /fnins eCollection Endocannabinoid System and Migraine Pain: An Update. Greco R(1). Among these, the endocannabinoid system (ES) has recently attracted considerable attention. Experimental and clinical data suggest indeed a.
and the System Migraines Endocannabinoid
This action has been exhibited only in people who abuse cannabis, suggesting that the brains of vulnerable individuals may present alterations that make them predisposed to development of dependence, even in the case of cannabis. Repeated reports suggest that the AEA system is involved in impulse control, self-identity, and ego perception. Psychotic disorders, in some cases present in cannabis users, would not be induced by cannabis directly, but provoked in susceptible individuals, because of the desensitisation of their AEA system.
Individuals with mental disorders, which remain permanently at a sub-clinical stage, display severe symptoms, such as hallucinations, social withdrawal and paranoia. Thus, AEA has an important role in several brain functions surrounding behaviour, but also memory, appetite, and sleep.
There is evidence that AEA inhibits the release of neurotransmitters regulating nociceptive pathways, as shown by high levels of the cannabinoid found in regions involved in pain transmission, such as skin receptors or dorsal root ganglia. Palmitoylethanolamide PEA , an endogenous fatty acid amide, is another substance that intervenes in the processes of neuroinflammation and is used in the management of neuropathic pain.
Recently, it has been shown to be successful at treating rare and severe types of headache, such as the nummular headache. ALIAmides are a biological, local antagonistic response to tissue damage injury , exerted by endogenous bioactive lipid products as needed on demand. In particular, PEA plays an important role in neuroinflammation, modulating the action of glial and mast cells and maintaining cellular homeostasis. Stimulation of the trigeminal vascular system causes a neuroinflammatory process with the release of neuropeptides, such as Substance P, 5-HT, and calcitonin gene-related peptide CGRP.
The formulation comprises tablets and microgranule sachets, the latter representing the ultramicronised form. Adverse effects have not been reported in any diseases treated with PEA. This is due to the active principle of PEA, a drug considered a nutraceutical, or an integrator of drugs.
PEA potentiates the activity of endogenous N-acylethanolamines with a mechanism, called entourage effect, that allows it to interact indirectly with the ECS. In summary, as biodynamic properties, PEA is an endogenous N-acylethanolamine that plays an important role in the resolution of neuro-inflammatory and algic processes. PEA acts on several non-neuronal cellular targets involved in the peripheral and central neuro-inflammatory processes that occur in acute and chronic pain conditions, as demonstrated in numerous preclinical studies and endorsed by a growing number of clinical studies.
Furthermore, on mechanisms of action, the anti-inflammatory, and analgesic effects of PEA are attributable to multiple mechanisms of action of receptor pleiotropic nature. At the cellular level, PEA acts primarily on two non-neuronal cells: The normalisation of excessive activation of these cells was involved in peripheral inflammation, spinal and central, characterised by chronic pain, and is the basis of the main effects of PEA.
These phytocannabinoids, literally plant-made cannabinoids, can have a profound effect on the body. While there are many plants that produce substances that act upon cannabinoid receptors, the cannabis plant is the only know to produce cannabidiol CBD. Excessive or deficient endocannabinoid levels can cause body systems to perform poorly, as can be seen by the cluster of illnesses believed to have a root in CECD. Research published in Neuroendocrinology Letters reviewed scientific publications to study the concept of CECD and the possibility that endocannabinoid deficiency can cause migraines.
The researchers also found cannabinoids block spinal, peripheral and gastrointestinal actions that promote the pain associated with headaches, fibromyalgia, irritable bowel syndrome and other conditions. In other words, increasing cannabinoid levels may reduce symptoms associated with clinical endocannabinoid deficiency syndrome. There are many factors that go into deciding on the ideal serving size and it would be irresponsible to ignore these variations between individuals.
If this amount does not have any impact, our analysis also suggests increasing the amount of CBD you are using by 25mg every weeks until you have found the results you are after. Similarly, if your condition gets worse, reduce the amount you are using by 25mg until you find the right balance. You can refer to our page on serving size for CBD for additional information. As always, before you start any natural supplementation regime, please consult with your primary care provider to make sure this is the best, and safest, path for you.
What is the Clinical Endocannabinoid Deficiency Syndrome? How Does the Endocannabinoid System Work? Moreover, they may also act on brain areas involved in emesis, such as the dorsal motor nucleus of the vagus Van Sickle et al.
The anti-migraine effects of the ES are not fully known, although some hypotheses were proposed. Clinical observations show that women migraine without aura or episodic tension-type headache have increased FAAH and endocannabinoid membrane transporter EMT activities in platelets, which is consistent with reduced AEA levels Cupini et al. In addition, women with episodic migraine have increased CB 1 receptor binding during the interictal period, as assessed by positron emission tomography; this increase is especially evident in brain regions that exert top-down influences to modulate pain Van der Schueren et al.
Variants in the CB 1 receptor gene increase the risk of migraine attack with nausea in life stress exposed subjects Juhasz et al. Recently Gouveia-Figueira et al. These contrasting findings may be related to higher inter-subject variability of EC levels in the evaluated cohorts or to a different migraine load on the populations investigated.
More consistent are the findings regarding the involvement of the ES in chronic migraine CM. These findings suggest an adaptive behavior induced by chronic headache per se , while medication overuse is apparently not related with EC activity.
Interestingly, serotonin levels were reduced in the MOH and CM patients, with lower values detected in females as compared to males Rossi et al. In this frame, it is worth mentioning that successful detoxification of MOH subjects is accompanied by a reduction in FAAH activity in platelets. This biochemical change is associated with the normalization of neurophysiological parameters that indicated a status of sensitization of the pain pathways Perrotta et al.
Inflammation and nerve injury cause changes in local AEA levels Jhaveri et al. The CB 1 receptor antagonist, AM, reversed this inhibitory activity, suggesting that CB 1 receptors may be implicated in the relationship between headache and dural blood vessel dilation and migraine mediators. Cortical spreading depression CSD is a self-propagating wave of neuronal hyperexcitability that has a role in migraine Goadsby, The trigeminal firing in the trigeminocervical complex induced by AEA inhibition is reversed after CB 1 receptor antagonism, thus suggesting that the central effects of AEA are principally CB 1 -mediated Akerman et al.
CB 1 receptor activation in the ventrolateral PAG, obtained with the administration of WIN55,, attenuates the activity evoked by dural stimulation in A-fiber neurons and the basal spontaneous activity in the trigeminocervical complex of rodent.
These findings suggest that, in the brainstem, ECs may provide to descending modulation upon basal trigeminovascular neuronal tone and A-fiber dural-nociceptive responses, Akerman et al.
NTG in rat causes an increased sensitivity to nociceptive tests and c-fos protein expression in brain areas nuclei involved in migraine pain transmission, such as NTC Greco et al. The use of this model by us and other groups has allowed the in-depth exploration of the mechanisms underlying the modulation of the ECs and the nociceptive activation of the TS during a migraine attack. In particular, we reported an increased FAAH activity in the hypothalamus and in the medulla area, where NTC neurons are located, and an up-regulation of CB 1 receptor binding sites in the same areas Greco et al.
The CB2 receptors activation in pain modulation has been considered in the past, showing analgesic activity in several models of pain Nackley et al. In our migraine model, we have also shown that CB 2 receptor activation significantly decreases nocifensive behavior of rats made hyperalgesic by NTG Greco et al.
Though the analgesic effects of cannabinoids are fairly well established, their use in therapy remains limited by their psychoactive properties Borgelt et al. Recent safety concerns about FAAH inhibitors turned out to be ungrounded, and due to off-target effects. Clearly, the successful development of compounds that modulate ECs tone for the pain relief in humans will hinge on the ability to separate psychotropic effects from therapeutic ones, and to control for potential off-target interactions.
Positive allosteric modulation of CB 1 receptor signaling may represent a safe analgesic alternative strategy that lacks tolerance, dependence and abuse liability Khurana et al.
Several studies show that also increasing ECs levels through the inhibition of catabolic enzymes, FAAH in particular, would decrease cannabimimetic side effects Piomelli et al. FAAH is contained in intracellular membranes of postsynaptic somata and dendrites of the mammalian brain Gulyas et al.
Manipulations of full-length and transmembrane-truncated FAAH variants have offered a characterization of mechanisms of action McKinney and Cravatt, In particular, these studies showed that, unlike most serine hydrolases, which use a histidine residue as a catalytic base, FAAH recruits a lysine to hydrolyze both amides and esters at equivalent rates Patricelli and Cravatt, In addition, mutant mice for FAAH enzyme in non-neuronal cells, but with FAAH activity conserved in peripheral and central neurons, have a phenotype in which basal nociceptive transmission is connected to the reduced responsiveness to pro-inflammatory mediators Cravatt et al.
Researchers suggest that AEA regulates nociceptive transmission primarily at the peripheral level Calignano et al. Numerous studies have shown that FAAH inhibition causes analgesia and reduces inflammation in animal models of acute inflammatory pain Kinsey et al. When considering that NTG is thought to activate meningeal trigeminovascular terminals via the local NO formation Reuter et al.
Accordingly, we have shown that a peripherally restricted FAAH inhibitor, the compound URB, inhibits NTG-induced nocifensive behaviors plantar and orofacial formalin test, tail flick test , neuronal activation in the NTC and locus coeruleus Greco et al.
In agreement with these data, URB decreases the c-Fos expression induced by plantar formalin injection in spinal cord regions involved in nociceptive processing by the CB 1 receptors Clapper et al. Thus, since URB acts only peripherally, it seems reasonable to hypothesize that its mechanism of action relies on the maintenance of higher levels of AEA released by nervous terminal located in the injured peripheral tissues hindpaw, upper lip, tail Agarwal et al. In agreement with this hypothesis, in vitro studies have shown that increased AEA tone, through the inhibition of its degradation or uptake, decreases the cytokines and NO levels Correa et al.
Pain is a heterogeneous condition and it should be treated as such. With its lack of sensitivity to standard analgesic medications Ong and De Felice, , migraine pain is a case in point and—perhaps better than most other forms of pain—underscores the need for tailored therapies. Future experiments should be aimed at unlocking the precise cellular mechanisms and neural circuits through which peripheral FAAH blockade exerts its analgesic effects in migraine pain, further exploring the ground for potential clinical trials.
The 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.
National Center for Biotechnology Information , U. Journal List Front Neurosci v. Published online Mar Zanaboni , 1, 2 Daniele Piomelli , 3 and Cristina Tassorelli 1, 2. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience.
Received Dec 21; Accepted Mar 5. 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 The trigeminovascular system TS activation and the vasoactive release from trigeminal endings, in proximity of the meningeal vessels, are considered two of the main effector mechanisms of migraine attacks. Introduction Migraine is one of the most disabling painful conditions and a very common disorder Global Burden of Disease, Endocannabinoid signaling EC signaling in the nervous system is different from those of the classic neurotransmission systems, where the depolarization of the presynaptic neuron causes neurotransmitters release which in turn activates their receptors on the postsynaptic neuron.
Relationship between ES dysregulation and migraine: Table 1 Potential effects of endocannabinoids on migraine pain. Open in a separate window.
Recent advances on FAAH inhibition in migraine pain Though the analgesic effects of cannabinoids are fairly well established, their use in therapy remains limited by their psychoactive properties Borgelt et al. Outlook Pain is a heterogeneous condition and it should be treated as such. Conflict of interest statement The 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.
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Review enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Cannabinoid CB1 receptor activation inhibits trigeminovascular neurons. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. Lack of association between the CT polymorphism of the neuronal nitric oxide synthase gene and migraine.
Supply and demand for endocannabinoids. Recent advances in migraine therapy. Comprehensive review of medicinal Marijuana, Cannabinoids, and therapeutic implications in medicine and headache: Headache 55 , — The endocannabinoid system and energy metabolism.
Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. Structural requirements for 5-HT2A and 5-HT1A serotonin receptor potentiation by the biologically active lipid oleamide. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 33 , —
What is the Clinical Endocannabinoid Deficiency Syndrome?
Among these, the endocannabinoid system (ES) has recently attracted Migraine is one of the most disabling painful conditions and a very. The recently discovered endocannabinoid system (ECS), which includes endocannabinoids and the proteins that metabolize and bind them, has been. Request PDF on ResearchGate | The endocannabinoid system and migraine | The recently discovered endocannabinoid system (ECS), which includes.