Migraine is a complex disorder characterized by recurrent episodes of headache, and is one of the most prevalent and disabling neurological disorders. A key feature of migraine is that various factors can trigger an attack, and this phenomenon provides a unique opportunity to investigate disease mechanisms by experimentally inducing migraine attacks. In this Review, we summarize the existing experimental models of migraine in humans, including those that exploit nitric oxide, histamine, neuropeptide and prostaglandin signalling. We describe the development and use of these models in the discovery of molecular pathways that are responsible for initiation of migraine attacks. Combining experimental human models with advanced imaging techniques might help to identify biomarkers of migraine, and in the ongoing search for new and better migraine treatments, human models will have a key role in the discovery of future targets for more-specific and more-effective mechanism-based antimigraine drugs.

Human models of migraine - short-term pain for long-term gain.

Migraine is a highly prevalent and disabling neurological disorder which is commonly linked with a broad range of psychiatric comorbidities, especially among subjects with migraine with aura or chronic migraine. Defining the exact nature of the association between migraine and psychiatric disorders and bringing out the pathophysiological mechanisms underlying the comorbidity with psychiatric conditions are relevant issues in the clinical practice. A systematic review of the most relevant studies about migraine and psychiatric comorbidity was performed using “PubMed”, “Scopus”, and “ScienceDirect” electronic databases from 1 January 1998 to 15 July 2018. Overall, 178 studies met our inclusion criteria and were included in the current review. According to the most relevant findings of our overview, the associations with psychiatric comorbidities are complex, with a bidirectional association of major depression and panic disorder with migraine. Importantly, optimizing the pharmacological and non-pharmacological treatment of either migraine or its psychiatric comorbidities might help clinicians to attenuate the burden of both these conditions. The available data highlight the need for a comprehensive evaluation of psychiatric disorders in migraine in order to promote an integrated model of care and carefully address the burden and psychosocial impairment related to psychiatric comorbidities in migraine.

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Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications.

Migraine, with and without aura (MA and MO), is a prevalent and complex neurovascular disorder that is likely to be influenced by multiple genes some of which may be capable of causing vascular changes leading to disease onset. This study was conducted to determine whether the ACE I/D gene variant is involved in migraine risk and whether this variant might act in combination with the previously implicated MTHFR C677T genetic variant in 270 migraine cases and 270 matched controls. Statistical analysis of the ACE I/D variant indicated no significant difference in allele or genotype frequencies (P > 0.05). However, grouping of genotypes showed a modest, yet significant, over-representation of the DD/ID genotype in the migraine group (88%) compared to controls (81%) (OR of 1.64, 95% CI: 1.00–2.69, P = 0.048). Multivariate analysis, including genotype data for the MTHFR C677T, provided evidence that the MTHFR (TT) and ACE (ID/DD) genotypes act in combination to increase migraine susceptibility (OR = 2.18, 95% CI: 1.15–4.16, P = 0.018). This effect was greatest for the MA subtype where the genotype combination corresponded to an OR of 2.89 (95% CI:1.47–5.72, P = 0.002). In Caucasians, the ACE D allele confers a weak independent risk to migraine susceptibility and also appears to act in combination with the C677T variant in the MTHFR gene to confer a stronger influence on the disease.

Genetic variants of angiotensin converting enzyme and methylenetetrahydrofolate reductase may act in combination to increase migraine susceptibility

Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (μ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1β and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (μ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the β-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the β-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that β-arrestin-2 acts as a functional component of the TLR4 pathway.

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Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility.

Animal models have provided a growing body of information about the pathophysiology of headaches and novel therapeutic targets. In recent years, experiments in awake animals have gained attention as more relevant headache models. Pain can be assessed in animals using behavioral alterations, which includes sensory-discriminative, affective-emotional and cognitive aspects. Spontaneous behavioral alterations such as increased grooming, freezing, eye blinking, wet dog shake and head shake and decreased locomotion, rearing, food or water consumption observed during pain episodes are oftentimes easy to translate into clinical outcomes, but are giving little information about the localization and modality of the pain. Evoked pain response such as tactile and thermal hypersensitivity measures are less translatable but gives more insight into mechanisms of action. Mechanical allodynia is usually assessed with von Frey monofilaments and dynamic aesthesiometer, and thermal allodynia can be evaluated with acetone evaporation test and Hargreaves’ test in animal models. Anxiety and depression are the most frequent comorbid diseases in headache disorders. Anxiety-like behaviors are evaluated with the open-field, elevated plus-maze or light/dark box tests. Interpretation of the latter test is challenging in migraine models, as presence of photophobia or photosensitivity can also be measured in light/dark boxes. Depressive behavior is assessed with the forced-swim or tail suspension tests. The majority of headache patients complain of cognitive symptoms and migraine is associated with poor cognitive performance in clinic-based studies. Cluster headache and tension type headache patients also exhibit a reversible cognitive dysfunction during the headache attacks. However, only a limited number of animal studies have investigated cognitive aspects of headache disorders, which remains a relatively unexplored aspect of these pathologies. Thus, the headache field has an excellent and growing selection of model systems that are likely to yield exciting advances in the future.

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Behavioral and cognitive animal models in headache research.

Epidemiological and clinical studies have demonstrated comorbidity between migraine and affective disorders. However, it is unclear whether chronic migraine can lead to affective disorders in other animals. A classical chronic migraine rat model (repeated dura mater inflammatory soup [IS] infusion) was used to evaluate depression and anxiety behaviour via weight, sucrose preference test, open field test and elevated plus maze test. We found that sucrose preference, locomotor and rearing behaviours, inner zoon distance percent, open-arm entries percent and serotonin and dopamine levels in the prefrontal cortex decreased significantly in the IS group compared with those in the control group; co-administration of low-dose amitriptyline ameliorated these deficits. However, no differences in weight, inner zone time percent, or open-arm time percent between the IS and control groups. These results were used to create new depression and anxiety scales to comprehensively assess and evaluate the degree of affective disorders in rats. Most of chronic migraine animals showed depression and anxiety like behaviors but a few didn’t. Most of the chronic migraine rats were present depression and anxiety like behaviors. The new scales we created are expected to use in the future studies to find out the potential mechanism of affective disorders’ ﻿comorbidity.

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Depression and anxiety behaviour in a rat model of chronic migraine

Objective Although nociceptive sensitisation is an important pathophysiological process in migraine and migraine chronification, its underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a pattern-recognition molecule, has a critical role in both neuropathic pain and morphine tolerance. The present study examined whether elements of the TLR4 pathway contribute to hyperalgesia induced by dural inflammation in rats. Methods A rat model of migraine was established by infusing a dural inflammatory soup. A group pretreated with TAK-242 was used to inhibit the activation of TLR4. The protein levels of TLR4 and its downstream molecules in the trigeminal pathway were examined by Western blot and immunofluorescence. The expression of activated microglia and astrocytes was also analysed. Levels of interleukin-1 beta, tumour necrosis factor-alpha, and brain-derived neurotrophic factor were measured by enzyme-linked immunosorbent assay. Results Acute inflammatory soup infusion induced time-dependent facial mechanical hyperalgesia, which was blocked by TAK-242 pretreatment. The inflammatory soup stimulus increased the production of TLR4 downstream molecules and interleukin-1 beta. Higher levels of microglia activation and brain-derived neurotrophic factor release were observed following the administration of the inflammatory soup but were alleviated by TAK-242. Conclusions These data suggest that the TLR4 signalling pathway promotes hyperalgesia induced by acute inflammatory soup delivery by stimulating the production of proinflammatory cytokines and activating microglia.

https://journals.sagepub.com/doi/pdf/10.1177/1744806918754612

Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine

Migraine Prevention Using Different Frequencies of Transcutaneous Occipital Nerve Stimulation: A Randomized Controlled Trial

Receptor activity modifying protein 1(RAMP1) is a key receptor subunit of calcitonin gene related peptide (CGRP) playing a critical role in migraine. But variations in RAMP1 gene have not been found to link with migraine. Still it is elusive that DNA methylation at RAMP1 promoter is associated with migraine. A total of 51 blood DNA samples from 26 patients with migraine and 25 matched healthy controls were collected, extracted and treated with bisulfate. Subsequently DNA methylation levels at RAMP1 promoter region were measured using Sequenom Mass ARRAY systems. Among 13 detected CpG sites or units at RAMP1 promoter region, there were no significant differences between the migraine and control groups, but indicating a low methylation trend overall in migraine group (total average methylation level: 8.41 % ±1.92 % vs. 9.90 % ± 3.88 %, p = 0.197). Stratification analysis showed that methylation level at (+25, +27, +31, related to the transcription start site) CpG unit was higher in migraineurs with migraine family history compared to those without (13.92 % ± 5.97 % vs. 8.77 % ± 6.61 %, p = 0.034), and methylation level at (+89, +94, +96) CpG unit was lower in migraine female than that in healthy female (2.18 % ± 1.91 % vs. 5.85 % ± 5.41 %, p = 0.02). For female with methylation level at (+89, +94, +96) CpG unit below 3.50 %, the probability of being a migraine patient was significantly higher than those with methylation level above the threshold (OR: 7.313; 95%CI: 1.439-37.164). This study provides the first evidence that DNA methylation at RAMP1 promoter might play a role in migraine. A low methylation trend overall was presented in migraine subjects, and two CpG units were observed to link with positive migraine family history and female migraine, respectively. Lower methlytion level at (+89, +94, +96) CpG unit may be a risk of migraine in females.

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DNA methylation of RAMP1 gene in migraine: an exploratory analysis

Interictal plasma pituitary adenylate cyclase-activating polypeptide levels are decreased in migraineurs but remain unchanged in patients with tension-type headache.

Wenjing Tang

Papers

Depression and anxiety behaviour in a rat model of chronic migraine

Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine

Migraine Prevention Using Different Frequencies of Transcutaneous Occipital Nerve Stimulation: A Randomized Controlled Trial

DNA methylation of RAMP1 gene in migraine: an exploratory analysis

Interictal plasma pituitary adenylate cyclase-activating polypeptide levels are decreased in migraineurs but remain unchanged in patients with tension-type headache.