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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., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective/background: It has been debated in the literature whether patients with idiopathic generalized epilepsy (IGE) have a distinctive, evening-oriented chronotype. The few questionnaire-based studies that are available in the literature have conflicting results. The aim of our study was to define chronotype in patients with IGE by determining dim light melatonin onset (DLMO)., Patients/methods: Twenty adults diagnosed with IGE (grand mal on awakening [GM] in 7 cases and juvenile myoclonic epilepsy in 13 cases) were investigated by means of a face-to-face semistructured sleep interview, Morningness-Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI) questionnaire, and a melatonin salivary test with DLMO determination. Eighteen healthy subjects (HC) and 28 patients affected with cryptogenic focal epilepsy (FE) served as controls., Results: The mean MEQ score was significantly lower in patients with IGE than that in patients with FE (49.1±5.9 versus 56.1±8.7 P<0.01) but not significantly lower than that in HC (49.1±5.9 versus 49.3±8.6). Midsleep on free days corrected for sleep duration did not differ significantly between the three subject groups (04:59±01:21h, 04:37±01:17h, 04:29±00:52h). The mean DLMO time in patients with IGE (22:13±01:34h) occurred 49min later than that in HC (21.24±1h), and the melatonin surge within the 30-minute time interval after DLMO in patients with IGE was significantly lower than that in HC (1.51±2.7 versus 3.8±3.6pg/mL P=0.045)., Conclusions: Subjective measures of chronotype do not indicate a definite evening-oriented chronotype in patients with IGE. However, the data concerning endogenous melatonin secretion indicate that patients with IGE tend to have a late circadian phase. Further studies are warranted in order to better define the late pattern of endogenous melatonin secretion in patients with IGE and to ascertain the role of this pattern in influencing behavioral chronotype in these subjects., (Copyright © 2016. Published by Elsevier Inc.)

Studies based on self-administered questionnaires indicate that most patients with epilepsy are morning-oriented. We aimed to investigate chronotype in patients with epilepsy with late-onset focal epilepsy by combining subjective data with dim light melatonin onset (DLMO) as an objective marker of the circadian phase. Sixty adult patients (mean age 46.5±13.8; 27 males) with late-onset focal epilepsy under pharmacological treatment were prospectively studied. Subjective chronotype was determined using the Morningness-Eveningness Questionnaire (MEQ) and circadian phase through analysis of salivary melatonin secretion, considering 3pg/ml as the dim light melatonin onset (DLMO) threshold. The mean MEQ score was significantly higher in the patients with epilepsy than in the controls, and significantly, more patients had a MEQ score indicative of the morning type (50.0% vs 30.0%, p=0.02). However, no significant differences were found in mean time of DLMO (21:38±01:21 vs 21:26±01:03; p=ns), and DLMO time was in the range indicative of an intermediate chronotype in both patients and controls. Sleep onset and sleep offset phase angles were significantly shorter in the patients. Patients whose global MEQ score identified them as morning types were significantly older than those with an intermediate or evening chronotype, and they had less social jet lag. No difference in epilepsy features and treatments was found between morning-oriented and nonmorning-oriented patients. Our analyses showed that the patients with epilepsy tended to be morning-oriented and to perceive themselves as morning types, even though this was not reflected in their DLMO values which did not differ significantly from those of controls and mostly fell within the intermediate chronotype range. Several factors may considerably influence subjective chronotype. We speculate that, in patients with epilepsy, the disease itself, prompting certain lifestyle choices, including a regular sleep schedule and early bedtime, may induce morning orientation and a morning-type self-perception., (Copyright © 2015 Elsevier Inc. All rights reserved.)