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Over the past two decades, a convergence of basic and clinical evidence has established the neuropeptide calcitonin-gene-related peptide (CGRP) as a key player in migraine. Although CGRP is a recognised neuromodulator of nociception, its mechanism of action in migraine remains elusive. In this review, we present evidence that led us to propose that...
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Context 1
... with CGRP increased the firing frequency of these neurons in response to AMPA, an effect that can be blocked by the peptide antagonist CGRP 8-37 (Refs 62, 63). Consequently, when CGRP levels are elevated in a susceptible individual, we hypothesise that there could be an amplification of otherwise ordinary sensory input to beyond a pain threshold (Fig. ...
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Objective:
The neuropeptide calcitonin gene-related peptide (CGRP) has now been established as a key player in migraine. However, the mechanisms underlying the reported elevation of CGRP in the serum and cerebrospinal fluid of some migraineurs are not known. A candidate mechanism is cortical spreading depression (CSD), which is associated with mig...
Citations
... 3,28 Other mouse studies demonstrated that CGRP may act both in the central nervous system (CNS) and periphery. 52,68,81 Potential targets may be meningeal nociceptors leading to vasodilatation, 79 the trigeminal system, cerebral blood vessels, and dura mater, 42 but peripheral CGRP may alter the trigeminovascular microenvironment, leading to central sensitization. 25,29,45,46,68,81 Here, we aimed to show neuroanatomical evidence that the EWcp/UCN1 may contribute to migraine. ...
The urocortin 1 (UCN1)–expressing centrally projecting Edinger–Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine triggers. Our study investigated EWcp's potential involvement in migraine. Using RNAscope in situ hybridization and immunostaining, we examined the expression of calcitonin gene–related peptide (CGRP) receptor components in both mouse and human EWcp and dorsal raphe nucleus (DRN). Tracing study examined connection between EWcp and the spinal trigeminal nucleus (STN). The intraperitoneal CGRP injection model of migraine was applied and validated by light–dark box, and von Frey assays in mice, in situ hybridization combined with immunostaining, were used to assess the functional–morphological changes. The functional connectivity matrix of EW was examined using functional magnetic resonance imaging in control humans and interictal migraineurs. We proved the expression of CGRP receptor components in both murine and human DRN and EWcp. We identified a direct urocortinergic projection from EWcp to the STN. Photophobic behavior, periorbital hyperalgesia, increased c-fos gene–encoded protein immunoreactivity in the lateral periaqueductal gray matter and trigeminal ganglia, and phosphorylated c-AMP–responsive element binding protein in the STN supported the efficacy of CGRP-induced migraine-like state. Calcitonin gene–related peptide administration also increased c-fos gene–encoded protein expression, Ucn1 mRNA, and peptide content in EWcp/UCN1 neurons while reducing serotonin and tryptophan hydroxylase-2 levels in the DRN. Targeted ablation of EWcp/UCN1 neurons induced hyperalgesia. A positive functional connectivity between EW and STN as well as DRN has been identified by functional magnetic resonance imaging. The presented data strongly suggest the regulatory role of EWcp/UCN1 neurons in migraine through the STN and DRN with high translational value.
... Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide encoded by CALCA gene and belongs to the calcitonin family of peptides together with adrenomedullin (AM), adrenomedullin 2 (AM2), also known as intermedin (IMD), amylin (AMY) and calcitonin [1]. CGRP is a neuropeptide and a potent vasodilator that plays multiple roles in physiological and pathophysiological conditions and processes including cardiovascular disease, wound healing, inflammation, cancer, lymphoedema and migraine [2][3][4][5][6][7][8][9]. Recent reports demonstrated the efficacy of drugs targeting the CGRP signalling axis for the treatment of migraine patients, but also revealed significant side effects such as inflammation and microvascular complications, including aberrant neovascularisation in the skin [10][11][12], highlighting the importance of studying cellular targets of CGRP in human tissues. ...
... In contrast, β-CGRP is primarily expressed in enteric nerves and the pituitary gland [30]. The CGRP receptor is formed by a multimer of a G-protein-coupled receptor called calcitonin-like receptor (CLR), the receptor component protein (RCP), and a transmembrane protein called receptor activity-modifying protein 1 (RAMP1) [31]. The CLR requires the RAMP1 for the binding of CGRP, and both of these components form the binding pocket, while the RCP is required for coupling the CGRP receptor to various intracellular signal transduction pathways [32,33]. ...
... Accumulating evidence suggests that CGRP ranks among the most important contributors in migraine pathogenesis, as demonstrated by its release upon stimulation of the trigeminal ganglion [37] coupled with evidence of CGRP-related modulation of the transmission of pain signals from the meninges to the CNS [31]. On clinical grounds, administering CGRP in migraineurs can evoke acute headaches, while inversely, CGRP release is suppressed by acute anti-migraine agents such as triptans. ...
Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7–100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning “missing information” arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology.
... This activation leads to the release of excitatory neurotransmitters, especially calcitonin gene-related peptide (CGRP) from dural afferent terminals (5). Substantial evidence now supports a crucial role of CGRP in the pathophysiology of migraine (6,7). Release of CGRP from nociceptors innervating the cranial meninges is thought to contribute to neurogenic vasodilation and to promote sensitization and activation of these fibers (7,8). ...
... Substantial evidence now supports a crucial role of CGRP in the pathophysiology of migraine (6,7). Release of CGRP from nociceptors innervating the cranial meninges is thought to contribute to neurogenic vasodilation and to promote sensitization and activation of these fibers (7,8). Sustained activation of peripheral nociceptors can elicit sensitization of the second-order neurons of the trigeminal nucleus caudalis (TNC) (3,4) resulting in enhanced nociceptive inputs to higher brain centers including the thalamus, hypothalamus and cortical sites, collectively manifesting as migraine pain (4,9). ...
Introduction
Migraines are the leading cause of disability in the United States, and the use of non-pharmaceutical treatments like osteopathic manipulative treatment (OMT) has shown promise. Despite its potential, the lack of mechanistic understanding has hindered widespread adoption. This study aims to investigate the efficacy of OMT in treating acute migraines and unravel its underlying mechanisms of action.
Methods
Female rats were subjected to a “two-hit” approach to induce migraine-like pain. This involved bilateral injections of Complete Freund's Adjuvant (CFA) into the trapezius muscle (1st hit) followed by exposure to Umbellulone, a human migraine trigger, on Day 6 post-CFA (2nd hit). Soft tissue and articulatory techniques were applied to the cervical region for acute abortive or repeated prophylactic treatment. Cutaneous allodynia and trigeminal system activation were assessed through behavioral tests and immunohistochemical staining.
Results
Following Umbellulone inhalation, CFA-primed rats exhibited periorbital and hind paw allodynia. Immediate application of OMT after Umbellulone inhalation as an abortive treatment partially alleviated cutaneous allodynia. With OMT applied thrice as a prophylactic measure, complete suppression of tactile hypersensitivity was observed. Prophylactic OMT also prevented the increase of c-fos signals in the trigeminal nucleus caudalis and the elevation of calcitonin gene-related peptide expression in trigeminal ganglia induced by CFA and Umbellulone exposure at 2 h post-inhalation.
Discussion
These findings provide mechanistic insights into OMT's migraine-relief potential and underscore its viability as a non-pharmacological avenue for managing migraines.
... Additionally, CSD can impact the glymphatic (perivascular) outflow, responsible for clearing waste material from the brain and potentially inducing additional cortical swelling [19]. Apart from such direct activation of mechanoreceptors, CSD can play an indirect role in mechanotransduction supporting meningeal neurogenic inflammation by triggering the release of CGRP [20,21] and substance P, activating mast cells [22,23]. The generated sterile neuroinflammation can sensitize dural local nerves to mechanical stimuli [24]. ...
Background
Migraine is a debilitating neurological disorder with pain profile, suggesting exaggerated mechanosensation. Mechanosensitive receptors of different families, which specifically respond to various mechanical stimuli, have gathered increasing attention due to their potential role in migraine related nociception. Understanding these mechanisms is of principal importance for improved therapeutic strategies. This systematic review comprehensively examines the involvement of mechanosensitive mechanisms in migraine pain pathways.
Methods
A systematic search across the Cochrane Library, Scopus, Web of Science, and Medline was conducted on 8th August 2023 for the period from 2000 to 2023, according to PRISMA guidelines. The review was constructed following a meticulous evaluation by two authors who independently applied rigorous inclusion criteria and quality assessments to the selected studies, upon which all authors collectively wrote the review.
Results
We identified 36 relevant studies with our analysis. Additionally, 3 more studies were selected by literature search. The 39 papers included in this systematic review cover the role of the putative mechanosensitive Piezo and K2P, as well as ASICs, NMDA, and TRP family of channels in the migraine pain cascade. The outcome of the available knowledge, including mainly preclinical animal models of migraine and few clinical studies, underscores the intricate relationship between mechanosensitive receptors and migraine pain symptoms. The review presents the mechanisms of activation of mechanosensitive receptors that may be involved in the generation of nociceptive signals and migraine associated clinical symptoms. The gender differences of targeting these receptors as potential therapeutic interventions are also acknowledged as well as the challenges related to respective drug development.
Conclusions
Overall, this analysis identified key molecular players and uncovered significant gaps in our understanding of mechanotransduction in migraine. This review offers a foundation for filling these gaps and suggests novel therapeutic options for migraine treatments based on achievements in the emerging field of mechano-neurobiology.
... Chronic paracetamol administration has been also shown to increase inflammatory cytokine expressions (IL1-α and TNF-α) in hippocampus however no association with pain was demonstrated in the same study [50]. CGRP is a prime molecule involved in migraine headache signaling and has a role in initiating the local inflammatory response [51]. CGRP levels are found to be high in the systemic circulation in migraine attacks and antagonism of circulating CGRP is a successful treatment in migraine patients [52,53]. ...
Objective
Medication overuse headache (MOH) is a secondary headache that accompanies chronic migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used analgesics worldwide and they are known to induce leaky gut. In this study, we aimed to investigate whether NSAID induced MOH is associated with altered circulating lipopolysaccharide binding protein (LBP) levels and inflammatory molecules.
Materials and methods
Piroxicam (10 mg/kg/day, po) for 5 weeks was used to induce MOH in female Sprague Dawley rats. Pain behavior was evaluated by periorbital withdrawal thresholds, head-face grooming, freezing, and head shake behavior. Serum samples and brain tissues were collected to measure circulating LBP, tight junction protein occludin, adherens junction protein vascular endothelial (VE)-cadherin, calcitonin gene-related peptide (CGRP), IL-6 levels and brain high mobility group box-1 (HMGB1) and IL-17 levels.
Results
Chronic piroxicam exposure resulted in decreased periorbital mechanical withdrawal thresholds, increased head-face grooming, freezing, and head shake behavior compared to vehicle administration. Serum LBP, CGRP, IL-6, IL-17, occludin, VE-cadherin levels and brain IL-17 and HMGB1 levels were significantly higher in piroxicam group compared to controls. Serum LBP was positively correlated with occludin (r = 0.611), VE-cadherin (r = 0.588), CGRP (r = 0.706), HMGB1 (r = 0.618) and head shakes (r = 0.921), and negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.740).
Conclusion
Elevated serum LBP, VE-cadherin and occludin levels indicating disrupted intestinal barrier function and leakage of LPS into the systemic circulation were shown in female rats with MOH. LPS induced low-grade inflammation and elevated nociceptive and/or pro-inflammatory molecules such as HMGB1, IL-6, IL-17 and CGRP may play a role in the development and maintenance of MOH. Interference with leaky gut and pro-inflammatory nociceptive molecules could also be a target for sustained management of MOH.
... 17 As such, inflammation of the meninges and meningeal vessels, rather than only their caliber, may be the key inciting mechanism. 18 The dura is a well-vascularized structure, which is densely innervated by pain fibers. 19 Some investigators have invoked a theory which incorporates both phenomena, suggesting that the dilation of dural vessels activates perivascular nerve fibers to release inflammatory factors. ...
... It has been confirmed that astrocytes also express CGRP receptor [136]. This indicates that astrocytes and neurons are involved in a positive feedback loop of CGRP synthesis-release process and maintain the increased inflammation and sensitization [137]. CGRP in astrocytes is significantly reduced in NTG treatment, suggesting that it is effective for migraine. ...
Migraine is a complex and multi-system dysfunction. The realization of its pathophysiology and diagnosis is developing rapidly. Migraine has been linked to gastrointestinal disorders such as irritable bowel syndrome and celiac disease. There is also direct and indirect evidence for a relationship between migraine and the gut-brain axis, but the exact mechanism is not yet explained. Studies have shown that this interaction appears to be influenced by a variety of factors, such as inflammatory mediators, gut microbiota, neuropeptides, and serotonin pathways. Recent studies suggest that immune cells can be the potential tertiary structure between migraine and gut-brain axis. As the hot interdisciplinary subject, the relationship between immunology and gastrointestinal tract is now gradually clear. Inflammatory signals are involved in cellular and molecular responses that link central and peripheral systems. The gastrointestinal symptoms associated with migraine and experiments associated with antibiotics have shown that the intestinal microbiota is abnormal during the attacks. In this review, we focus on the mechanism of migraine and gut-brain axis, and summarize the tertiary structure between immune cells, neural network, and gastrointestinal tract.
... Tendon injury promotes the growth of peripheral nerve fibers in the tendon sheath into the tendon parenchyma, which produces neuropeptides (e.g., substance P (SP) and calcitonin gene-related peptide (CGRP)) to regulate the function of immune and stromal cells [88][89][90]. Mast cells express a variety of neuropeptide receptors, such as neurokinin 1 receptors (bound with SP), calcitonin receptor-like receptors, and glutamate receptors, and upon binding to ligands, inflammatory pathways are activated, causing the release of cytokines (e.g., TNF-α and IL-8) and chemokines [79,[91][92][93]. Mast cell-derived neurotransmitters, such as histamine and dopamine, also in turn act on neurons [94]. ...
Background:
Tendinopathy is a common motor system disease that leads to pain and reduced function. Despite its prevalence, our mechanistic understanding is incomplete, leading to limited efficacy of treatment options. Animal models contribute significantly to our understanding of tendinopathy and some therapeutic options. However, the inadequacies of animal models are also evident, largely due to differences in anatomical structure and the complexity of human tendinopathy. Different animal models reproduce different aspects of human tendinopathy and are therefore suitable for different scenarios. This review aims to summarize the existing animal models of tendinopathy and to determine the situations in which each model is appropriate for use, including exploring disease mechanisms and evaluating therapeutic effects.
Methods:
We reviewed relevant literature in the PubMed database from January 2000 to December 2022 using the specific terms ((tendinopathy) OR (tendinitis)) AND (model) AND ((mice) OR (rat) OR (rabbit) OR (lapin) OR (dog) OR (canine) OR (sheep) OR (goat) OR (horse) OR (equine) OR (pig) OR (swine) OR (primate)). This review summarized different methods for establishing animal models of tendinopathy and classified them according to the pathogenesis they simulate. We then discussed the advantages and disadvantages of each model, and based on this, identified the situations in which each model was suitable for application.
Results:
For studies that aim to study the pathophysiology of tendinopathy, naturally occurring models, treadmill models, subacromial impingement models and metabolic models are ideal. They are closest to the natural process of tendinopathy in humans. For studies that aim to evaluate the efficacy of possible treatments, the selection should be made according to the pathogenesis simulated by the modeling method. Existing tendinopathy models can be classified into six types according to the pathogenesis they simulate: extracellular matrix synthesis-decomposition imbalance, inflammation, oxidative stress, metabolic disorder, traumatism and mechanical load.
Conclusions:
The critical factor affecting the translational value of research results is whether the selected model is matched with the research purpose. There is no single optimal model for inducing tendinopathy, and researchers must select the model that is most appropriate for the study they are conducting.
The translational potential of this article:
The critical factor affecting the translational value of research results is whether the animal model used is compatible with the research purpose. This paper provides a rationale and practical guide for the establishment and selection of animal models of tendinopathy, which is helpful to improve the clinical transformation ability of existing models and develop new models.
... It seems that CGRP probably has important roles in migraine both peripherally, via its release from sensory neurons innervating blood vessels, causing vasodilatation and peripheral sensitisation. Similarly, a role through central mechanisms via expression in several brain areas important in migraine, therefore contributing to central sensitisation, sensory aversion, and CSD [188], may be of equal, or perhaps, greater, importance. ...
Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future.
