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.

Effects of the Dual FAAH/MAGL Inhibitor AKU-005 on Trigeminal Hyperalgesia in Male Rats.

The inhibition of endocannabinoid hydrolysis by enzymatic inhibitors may interfere with mechanisms underlying migraine-related pain. The dual FAAH/MAGL inhibitor AKU-005 shows potent inhibitory activity in vitro. Here, we assessed the effect of AKU-005 in a migraine animal model based on nitroglycerin (NTG) administration. Male rats were treated with AKU-005 (0.5 mg/kg, i.p.) or vehicle 3 h after receiving NTG (10 mg/kg, i.p.) or NTG vehicle. One hour later, rats were subjected to the open field test followed by the orofacial formalin test. At the end of the test, we collected serum samples for assessing calcitonin gene-related peptide (CGRP) levels as well as meninges, trigeminal ganglia, and brain areas to assess mRNA levels of CGRP and pro-inflammatory cytokines, and endocannabinoid and related lipid levels. AKU-005 reduced NTG-induced hyperalgesia during the orofacial formalin test but did not influence NTG-induced changes in the open field test. It significantly reduced serum levels of CGRP, CGRP, and pro-inflammatory cytokine mRNA levels in the meninges, trigeminal ganglia, and central areas. Surprisingly, AKU-005 caused no change in endocannabinoids and related lipids in the regions evaluated. The present findings suggest that AKU-005 may have anti-migraine effects by reducing CGRP synthesis and release and the associated inflammatory events. This effect, however, does not seem mediated via an interference with the endocannabinoid pathway.

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia.

Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood-brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms.

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.

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.

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.