Vascular actions of peripheral CGRP in migraine-like photophobia in mice.
Ontology highlight
ABSTRACT: Background
Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice.Methods
Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay.Results
Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion.Conclusion
We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.
SUBMITTER: Mason BN
PROVIDER: S-EPMC7785273 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Migraine headache is uniquely exacerbated by light. Using psychophysical assessments in patients with normal eyesight we found that green light exacerbates migraine headache significantly less than white, blue, amber or red lights. To delineate mechanisms, we used electroretinography and visual evoked potential recording in patients, and multi-unit recording of dura- and light-sensitive thalamic neurons in rats to show that green activates cone-driven retinal pathways to a lesser extent than white, blue and red; that thalamic neurons are most responsive to blue and least responsive to green; and that cortical responses to green are significantly smaller than those generated by blue, amber and red lights. These findings suggest that patients' experience with colour and migraine photophobia could originate in cone-driven retinal pathways, fine-tuned in relay thalamic neurons outside the main visual pathway, and preserved by the cortex. Additionally, the findings provide substrate for the soothing effects of green light.
| S-EPMC4939697 | biostudies-other
Project description:Backgroundthe interest of clinical reaseach in polymorphisms and epigenetics in migraine has been growing over the years. Due to the new era of preventative migraine treatment opened by monoclonal antibodies (mAbs) targeting the signaling of the calcitonin-gene related peptide (CGRP), the present systematic review aims at identifying genetic variants occurring along the CGRP pathway and at verifying whether these can affect the clinical features and the course of disease and the responsiveness of patients to therapy.Methodsthe literature search has been conducted consulting the most relevant scientific databases, i.e. PubMed/MEDLINE, Scopus, Web of Science, the Human Genome Epidemiology (HuGE) Published Literature database (Public Health Genomics Knowledge Base) and Clinicaltrials.gov from database inception until April 1, 2021. The process of identification and selection of the studies included in the analysis has followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses and the guidance from the Human Genome Epidemiology Network for reporting gene-disease associations.Resultsthe search has retrieved 800 results, among which only 7 studies have met the eligibility criteria for inclusion in the analysis. The latter are case-control studies of genetic association and an exploratory analysis and two polymorphisms have been detected as the most recurring: the rs3781719 (T > C) of the CALC A gene encoding CGRP and the rs7590387 of the gene encoding the receptor activity-modifying protein (RAMP) 1 (C > G). Only one study assessing the methylation pattern with regard to CGRP pathway has been found from the search. No genetic association studies investigating the possible effect of genetic variants affecting CGRP signaling on the responsiveness to the most recent pharmacological approaches, i.e. anti-CGRP(R) mAbs, gepants and ditans, have been published. According to the Human Genome Epidemiology (HuGE) systematic reviews and meta-analyses risk-of-bias score for genetic association studies, the heterogeneity between and across studies and the small sample size do not allow to draw conclusions and prompt future studies.Conclusionsadequately powered, good quality genetic association studies are needed to understand the impact of genetic variants affecting the pathway of CGRP on migraine susceptibility and clinical manifestation and to predict the response to therapy in terms of efficacy and safety.
| S-EPMC8325208 | biostudies-literature
Project description:Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.
| S-EPMC7382295 | biostudies-literature
Project description:BackgroundCircadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases.MethodsMale and female mice of the outbred CD1 strain were administered vehicle (PBS) or CGRP (0.1 mg/kg, i.p.) to induce migraine-like symptoms. Animals were tested for activity (homecage movement and voluntary wheel running), light aversive behavior, and spontaneous pain at different times of the day and night.ResultsPeripheral administration of CGRP decreased the activity of mice during the first hour after administration, induced light aversive behavior, and spontaneous pain during that same period of time. Both phenotypes were observed no matter what time of the day or night they were assessed.ConclusionsA decrease in wheel activity is an additional clinically relevant phenotype observed in this model, which is reminiscent of the reduction in normal physical activity observed in migraine patients. The ability of peripheral CGRP to induce migraine-like symptoms in mice is independent of the phase of the circadian cycle. Therefore, preclinical assessment of migraine-like phenotypes can likely be done during the more convenient inactive phase of mice.
| S-EPMC8243868 | biostudies-literature
Project description:OBJECTIVE:The goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene-related peptide (CGRP) within the context of the trigeminovascular system. BACKGROUND:Migraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system. DESIGN:This narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points. RESULTS:The trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second-order neurons. A shift in central sensitization from activity-dependent to activity-independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder. CONCLUSIONS:CGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Additionally, the potential exists that this therapeutic strategy may also alleviate cluster headache as well.
| S-EPMC6593989 | biostudies-literature
Project description:BackgroundThe clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP - fremanezumab, galcanezumab and eptinezumab - and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature.MethodsTo gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays.ResultsErenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses.ConclusionThe therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.
| S-EPMC8054164 | biostudies-literature
Project description:OBJECTIVE:Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine. BACKGROUND:The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs). METHODS:This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks. RESULTS:The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ?1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ?2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal. CONCLUSION:Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.
| S-EPMC7496574 | biostudies-literature
Project description:BackgroundChronic migraine is a highly debilitating condition that is often difficult to manage, particularly in the presence of medication overuse headache. Drugs targeting the calcitonin gene-related peptide (CGRP), or its receptor have shown promising results in treating this disorder.MethodsWe searched Pubmed and Embase to identify randomized clinical trials and real-world studies reporting on the use of medication targeting the calcitonin gene-related peptide in patients with chronic migraine.ResultsA total of 270 records were identified. Nineteen studies qualified for the qualitative analysis. Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6-61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29-88% of the patients stopped medication overuse. Obesity seems to be the main negative predictor of response to anti-CGRP mAbs. There is no evidence to suggest the superiority of one anti-CGRP mAb. Despite the lack of strong evidence, the combination of anti-CGRP medication with onabotulinumtoxinA in chronic migraine is likely to bring benefits for resistant cases. Atogepant is the first gepant to demonstrate a significant decrease in monthly migraine days compared to placebo in a recent trial. Further, anti-CGRP mAb and gepants have a good safety profile.ConclusionThere is strong evidence from randomized trials and real-world data to suggest that drugs targeting CGRP are a safe and effective treatment for chronic migraine.
| S-EPMC10996229 | biostudies-literature
Project description:Migraine is a highly prevalent, severe, and disabling neurological condition with a significant unmet need for effective acute therapies. Patients (~50%) are dissatisfied with their currently available therapies. Calcitonin gene-related peptide (CGRP) has emerged as a key neuropeptide involved in the pathophysiology of migraines. As reviewed in this manuscript, a number of small molecule antagonists of the CGRP receptor have been developed for migraine therapy. Incredibly, the majority of the clinical trials conducted have proven positive, demonstrating the importance of this signalling pathway in migraine. Unfortunately, a number of these molecules raised liver toxicity concerns when used daily for as little as 7 days resulting in their discontinuation. Despite the clear safety concerns, clinical trial data suggests that their intermittent use remains a viable and safe alternative, with 2 molecules remaining in clinical development (ubrogepant and rimegepant). Further, these proofs of principle studies identifying CGRP as a viable clinical target have led to the development of several CGRP or CGRP receptor-targeted monoclonal antibodies that continue to show good clinical efficacy.
| S-EPMC5935646 | biostudies-literature
Project description:ObjectiveMigraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female-specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges.MethodsProlactin, CGRP, and receptor antagonists CGRP8-37 or Δ1-9-G129R-hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back-labeled trigeminal ganglia (TG) neurons was used to assess PRL-induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured.ResultsWe found that dural PRL produced sustained and long-lasting migraine-like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little-to-no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8-37 decreases migraine-like responses to dural PRL. Reciprocally, Δ1-9-G129R-hPRL attenuates dural CGRP-induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine-like responses to dural CGRP.InterpretationThis CGRP-PRL interaction in the meninges is a mechanism by which these peptides could produce female-selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129-1144.
| S-EPMC8195469 | biostudies-literature