A Narrative Review of Intestinal Microbiota's Impact on Migraine with Psychopathologies.

Migraine is a common and debilitating neurological disorder characterized by the recurrent attack of pulsating headaches typically localized on one side of the head associated with other disabling symptoms, such as nausea, increased sensitivity to light, sound and smell and mood changes. Various clinical factors, including the excessive use of migraine medication, inadequate acute treatment and stressful events, can contribute to the worsening of the condition, which may evolve to chronic migraine, that is, a headache present on >15 days/month for at least 3 months. Chronic migraine is frequently associated with various comorbidities, including anxiety and mood disorders, particularly depression, which complicate the prognosis, response to treatment and overall clinical outcomes. Emerging research indicates a connection between alterations in the composition of the gut microbiota and mental health conditions, particularly anxiety and depression, which are considered disorders of the gut-brain axis. This underscores the potential of modulating the gut microbiota as a new avenue for managing these conditions. In this context, it is interesting to investigate whether migraine, particularly in its chronic form, exhibits a dysbiosis profile similar to that observed in individuals with anxiety and depression. This could pave the way for interventions aimed at modulating the gut microbiota for treating difficult-to-manage migraines.

Expression of miR-155 in monocytes of people with migraine: association with phenotype, disease severity and inflammatory profile.

BACKGROUND: miR-155 is involved in the generation and maintenance of inflammation and pain, endothelial function and immune system homeostasis, all functions that are relevant for migraine. The present study aims to assess the levels of miR-155 in migraine subtypes (episodic and chronic) in comparison to age- and sex-matched healthy controls. METHODS: This is a cross-sectional, controlled, study involving three study groups: I) episodic migraine (n = 52, EM), II) chronic migraine with medication overuse (n = 44, CM-MO), and III) healthy controls (n = 32, HCs). We assessed the interictal gene expression levels of miR-155, IL-1ß, TNF-α, and IL-10 in peripheral blood monocytes using rtPCR. The monocytic differentiation toward the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes was assessed in circulating monocytes with flow cytometry analysis and cell sorting. RESULTS: miR-155 gene expression was higher in CM-MO group (2.68 ± 2.47 Relative Quantification - RQ) when compared to EM group (1.46 ± 0.85 RQ, p = 0.006) and HCs (0.44 ± 0.18 RQ, p = 0.001). In addition, miR-155 gene expression was higher in EM group when compared to HCs (p = 0.001). A multivariate analysis confirmed the difference between EM and CM-MO groups after correction for age, sex, smoking habit, preventive treatment, aura, presence of psychiatric or other pain conditions. We found higher gene expression of IL-1ß, TNF-α, and lower gene expression of IL-10 in migraine participants when compared to HCs (p = 0.001 for all comparisons). TNF-α and IL-10 genes alterations were more prominent in CM-MO when compared to EM participants (p = 0.001). miR-155 positively correlated with IL-1ß (p = 0.001) and TNF-α (p = 0.001) expression levels. Finally, in people with CM-MO, we described an up-regulated percentage of events in both M1 and M2 monocytic profiles. CONCLUSIONS: Our study shows for the first time a specific profile of activation of miR-155 gene expression levels in monocytes of selected migraine subpopulations, more pronounced in subjects with CM-MO. Interestingly, mir-155 expression correlated with markers of activation of the inflammatory and immune systems. The CM-MO subpopulation showed a peculiar increase of both pro-inflammatory and anti-inflammatory monocytes which worths further investigation. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . (NCT05891808).

Activity of FAAH-Inhibitor JZP327A in an Experimental Rat Model of Migraine.

Increased anandamide levels via fatty acid amide hydrolase (FAAH) inhibition can decrease the pronociceptive responses and inflammatory mediators in animal models of migraine. Here, we profile the pharmacological activity of the FAAH inhibitor JZP327A, a chiral 1,3,4-oxadiazol-2(3H)-one compound, in the mediation of spontaneous and nocifensive behaviour in the animal models of migraine based on nitroglycerin (NTG) administration. JZP327A (0.5 mg/kg, i.p.) or vehicle was administered to male rats 3 h after NTG (10 mg/kg, i.p.) or NTG vehicle injection. The rats were then exposed to the open field test and an orofacial formalin test 1 h later. The levels of endocannabinoids and lipid-related substances, and the expression of pain and inflammatory mediators were evaluated in cranial tissues and serum. The findings show that JZP327A did not affect NTG-induced changes in the spontaneous behaviour of rats, while it inhibited NTG-induced hyperalgesia at the orofacial formalin test. Furthermore, JZP327A dramatically decreased the gene expression of calcitonin gene-related peptide (CGRP), tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the trigeminal ganglia and medulla-pons, while it did not change endocannabinoids or lipids levels nor CGRP serum levels in the same tissues. These data suggest an anti-hyperalgesic role for JZP327A in the NTG model, which is mediated by the inhibition of the inflammatory cascade of events. This activity does not seem mediated by a change in the levels of endocannabinoids and lipid amides.

Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings.

In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.

Characterization of the biochemical and behavioral effects of cannabidiol: implications for migraine.

Cannabidiol (CBD) is the main pharmacologically active phytocannabinoid. CBD exerts an analgesic effect in several pain models, does not have side effects and has low toxicity. The data about CBD mechanisms of action in pain and its therapeutic potential in this area are limited. Here, we tested CBD effects in animal models specific for migraine. We assayed CBD distribution in plasma and in cranial areas related to migraine pain in male Sprague Dawley rats treated chronically (5 days). Successively, we tested CBD activity on the behavioral and biochemical effects induced in the acute and the chronic migraine animal models by nitroglycerin (NTG) administration. In the acute migraine model, rats received CBD (15 mg or 30 mg/kg, i.p) 3 h after NTG (10 mg/kg i.p.) or vehicle injection. In the chronic migraine model, rats were treated with CBD and NTG every other day over nine days with the following doses: CBD 30 mg/kg i.p., NTG 10 mg/kg i.p. We evaluated behavioral parameters with the open field and the orofacial formalin tests. We explored the fatty acid amide hydrolase gene expression, cytokines mRNA and protein levels in selected brain areas and CGRP serum level. CBD levels in the meninges, trigeminal ganglia, cervical spinal cord, medulla pons, and plasma were higher 1 h after the last treatment than after 24 h, suggesting that CBD penetrates but does not accumulate in these tissues. In the acute model, CBD significantly reduced NTG-induced trigeminal hyperalgesia and CGRP and cytokine mRNA levels in peripheral and central sites. In the chronic model, CBD caused a significant decrease in NTG-induced IL-6 protein levels in the medulla-pons, and trigeminal ganglion. It also reduced CGRP serum levels. By contrast, CBD did not modulate TNF-alpha protein levels and fatty acid amide hydrolase (FAAH) gene expression in any of investigated areas. In both experimental conditions, there was no modulation of anxiety, motor/exploratory behavior, or grooming. These findings show that CBD reaches brain areas involved in migraine pain after systemic administration. They also show for the first time that CBD modulates migraine-related nociceptive transmission, likely via a complex signaling mechanism involving different pathways.

The endocannabinoid system and related lipids as potential targets for the treatment of migraine-related pain.

BACKGROUND: Migraine is a complex and highly disabling neurological disease whose treatment remains challenging in many patients, even after the recent advent of the first specific-preventive drugs, namely monoclonal antibodies that target calcitonin gene-related peptide. For this reason, headache researchers are actively searching for new therapeutic targets. Cannabis has been proposed for migraine treatment, but controlled clinical studies are lacking. A major advance in cannabinoid research has been the discovery of the endocannabinoid system (ECS), which consists of receptors CB1 and CB2; their endogenous ligands, such as N-arachidonoylethanolamine; and the enzymes that catalyze endocannabinoid biosynthesis or degradation. Preclinical and clinical findings suggest a possible role for endocannabinoids and related lipids, such as palmitoylethanolamide (PEA), in migraine-related pain treatment. In animal models of migraine-related pain, endocannabinoid tone modulation via inhibition of endocannabinoid-catabolizing enzymes has been a particular focus of research. METHODS: To conduct a narrative review of available data on the possible effects of cannabis, endocannabinoids, and other lipids in migraine-related pain, relevant key words were used to search the PubMed/MEDLINE database for basic and clinical studies. RESULTS: Endocannabinoids and PEA seem to reduce trigeminal nociception by interacting with many pathways associated with migraine, suggesting a potential synergistic or similar effect. CONCLUSIONS: Modulation of the metabolic pathways of the ECS may be a basis for new migraine treatments. The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area. Multiple molecules related to the ECS or to allosteric modulation of CB1 receptors have emerged as potential therapeutic targets in migraine-related pain. The complexity of the ECS calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development.

Oculo-vestibular signs in experimentally induced migraine attacks: an exploratory analysis.

Vestibular symptoms accompanying headache are quite common in migraine patients. Based on the association of vertigo with migraine, vestibular migraine was included in the appendix of the 3rd edition of the International Classification of Headache Disorders as a possible migraine subtype worthy of further investigation. In this post hoc, exploratory analysis, we investigated the occurrence of oculo-vestibular signs (OVSs) during experimentally induced migraine attacks in 24 episodic migraine patients and 19 healthy controls exposed to sublingual nitroglycerin (NTG - 0.9 mg). A comprehensive clinical examination was performed at baseline, at the onset of the migraine-like attack, and immediately before hospital discharge (180 minutes after NTG administration). Three of the 13 migraine patients who developed a spontaneous-like migraine attack during the hospital observation period (23.1%) also developed OVSs during the induction test. Noteworthy, none of the patients with a negative induction test developed OVSs and no OVSs were reported in healthy subjects at any time point. The exploratory nature of our study does not allow to draw definite conclusions on the possible implications of a vestibular dysfunction in migraine pathophysiology. Our results however suggest that NTG administration may lend itself to investigate vestibular dysfunction in migraine, at least in a subset of patients. The present findings represent a starting point for designing future ad hoc and well-powered studies.

Modulation of Glia Activation by TRPA1 Antagonism in Preclinical Models of Migraine.

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM_12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM_12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM_12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM_12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation.

Potentiation of endocannabinoids and other lipid amides prevents hyperalgesia and inflammation in a pre-clinical model of migraine.

Targeting fatty acid amide hydrolase (FAAH) is a promising therapeutic strategy to combat certain forms of pain, including migraine headache. FAAH inhibitors, such as the O-biphenyl-3-yl carbamate URB597, have been shown to produce anti-hyperalgesic effects in animal models of migraine. The objective of this study was to investigate the behavioral and biochemical effects of compounds ARN14633 and ARN14280, two URB597 analogs with improved solubility and bioavailability, in a migraine-specific rat model in which trigeminal hyperalgesia is induced by nitroglycerin (NTG) administration. ARN14633 (1 mg/kg, i.p.) and ARN14280 (3 mg/kg, i.p.) were administered to adult male Sprague-Dawley rats 3 hours after NTG injection. One hour after the administration of either compound, rats were subjected to the orofacial formalin test. ARN14633 and ARN14280 attenuated NTG-induced nocifensive behavior and reduced transcription of genes encoding neuronal nitric oxide synthase, pain mediators peptides (calcitonin gene-related peptide, substance P) and pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta and 6) in the trigeminal ganglion, cervical spinal cord and medulla. Finally, both compounds strongly elevated levels of endocannabinoids and/or other FAAH substrates in cervical spinal cord and medulla, and, to a lesser extent, in the trigeminal ganglia. The results indicate that the novel global FAAH inhibitors ARN14633 and ARN14280 elicit significant anti-hyperalgesic effects in a migraine-specific animal model and inhibit the associated peptidergic-inflammatory response. Although the precise mechanism underlying these effects remains to be elucidated, our results support further investigational studies of FAAH blockade as a potential therapeutic strategy to treat migraine conditions.

Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine.

Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia - an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.