Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia

Cephalalgia ◽  
2013 ◽  
Vol 34 (8) ◽  
pp. 594-604 ◽  
Author(s):  
R Greco ◽  
AS Mangione ◽  
F Siani ◽  
F Blandini ◽  
M Vairetti ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Formalin Test ◽  
Tail Flick ◽  
Cgrp Receptor ◽  
Tail Flick Test ◽  
Nociceptive Transmission ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Cgrp Receptor Antagonist ◽  
Trigeminal Nerves

Background The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. Aim The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. Results MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30–60 minutes before) NTG. Conclusion These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.

scholarly journals CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured

Cephalalgia ◽  
2017 ◽  
Vol 38 (3) ◽  
pp. 437-451 ◽  
Author(s):  
Christopher S Walker ◽  
Ann C Raddant ◽  
Michael J Woolley ◽  
Andrew F Russo ◽  
Debbie L Hay
Keyword(s):  
Receptor Antagonist ◽  
Signalling Pathway ◽  
Cgrp Receptor ◽  
Trigeminovascular System ◽  
Antagonist Activity ◽  
Creb Phosphorylation ◽  
Signalling Molecules ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Cgrp Receptor Antagonist

Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the trigeminovascular system and is believed to play an important role in migraine. CGRP activates two receptors that are both present in the trigeminovascular system; the CGRP receptor and the amylin 1 (AMY1) receptor. CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant (MK-0974), can treat migraine. This study aimed to determine the effectiveness of these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) neurons and transfected CGRP and AMY1 receptors in Cos7 cells, to better understand their mechanism of action. Methods CGRP stimulation of four intracellular signalling molecules relevant to pain (cAMP, CREB, p38 and ERK) were examined in rat TG neurons and compared to transfected CGRP and AMY1 receptors in Cos7 cells. Results In TG neurons, olcegepant displayed signal-specific differences in antagonism of CGRP responses. This effect was also evident in transfected Cos7 cells, where olcegepant blocked CREB phosphorylation more potently than expected at the AMY1 receptor, suggesting that the affinity of this antagonist can be dependent on the signalling pathway activated. Conclusions CGRP receptor antagonist activity appears to be assay-dependent. Thus, these molecules may not be as selective for the CGRP receptor as commonly reported.

Novel Therapies in Acute Migraine Management: Small-Molecule Calcitonin Gene-Receptor Antagonists and Serotonin 1F Receptor Agonist

2020 ◽  
pp. 106002802096357
Author(s):  
Kayla Rena Joyner ◽  
Kelsey Woods Morgan
Keyword(s):  
Receptor Antagonist ◽  
English Language ◽  
Data Extraction ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Study Selection ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Cgrp Receptor Antagonist

Objective To review the efficacy, safety, and cost of 3 newly approved agents—ubrogepant, lasmiditan, and rimegepant—representing 2 therapeutic classes, calcitonin gene-related peptide (CGRP) receptor antagonist and serotonin 1F (5-HT1F) agonists, for the acute treatment of migraine with or without aura. Data Sources The Institute of Health US National Library of Medicine Clinical Trials, PubMed, and Cochrane databases were queried. Abstracts, journal articles, and other relevant sources published or present were reviewed. Search terms included the following: ubrogepant, MK-1602, Ubrelvy®, rimegepant, Nurtec®, BHV-3000, BMS-927711, lasmiditan, Reyvow®, LY573144. Study Selection and Data Extraction Relevant English-language articles from June 30, 2010, to August 31, 2020, were evaluated and included in the narrative. Data Synthesis CGRP receptor antagonists, ubrogepant and rimegepant, achieved 2-hour pain freedom and freedom from the most bothersome migraine symptom (MBS) at 2 hours. Both agents were well tolerated, with adverse effects similar to placebo. Lasmiditan, a 5-HT1F receptor antagonist, also improved 2-hour pain freedom and freedom from the MBS at 2 hours. Lasmiditan is associated with dizziness, paresthesia, somnolence, nausea, fatigue, and lethargy. Relevance to Patient Care and Clinical Practice Ubrogepant, rimegepant, and lasmiditan represent a new and exciting chapter in acute migraine therapy. To date, no head-to-head studies have compared these agents with the triptans. Ubrogepant and lasmiditan are effective in triptan nonresponders. None of the 3 agents is contraindicated in cardiovascular disease, unlike the triptans. Conclusions Based on available data, ubrogepant, rimegepant, and lasmiditan should be reserved as second-line therapy and may be safe in patients with cardiovascular risk. Lasmiditan’s adverse effect profile may limit its use.

The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1

2012 ◽  
Vol 22 (14) ◽  
pp. 4723-4727 ◽  
Author(s):  
Xiaojun Han ◽  
Rita L. Civiello ◽  
Charles M. Conway ◽  
Deborah A. Cook ◽  
Carl D. Davis ◽  
...  
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists

Inhibition of monoacylglycerol lipase: Another signalling pathway for potential therapeutic targets in migraine?

Cephalalgia ◽  
2017 ◽  
Vol 38 (6) ◽  
pp. 1138-1147 ◽  
Author(s):  
Rosaria Greco ◽  
Chiara Demartini ◽  
Anna Maria Zanaboni ◽  
Laura Berliocchi ◽  
Daniele Piomelli ◽  
...  
Keyword(s):  
Formalin Test ◽  
Endocannabinoid System ◽  
Tail Flick ◽  
Monoacylglycerol Lipase ◽  
Neuronal Activation ◽  
Nociceptive Behavior ◽  
Tail Flick Test ◽  
Area Of Interest ◽  
Key Enzyme ◽  
Hydrolysis Of

Background Drugs that modulate endocannabinoid signalling are effective in reducing nociception in animal models of pain and may be of value in the treatment of migraine. Methods We investigated the anti-nociceptive effects of inhibition of monoacylglycerol lipase (MGL), a key enzyme in the hydrolysis of the 2-arachidonoylglycerol, in a rat model of migraine based on nitroglycerin (NTG) administration. We evaluated c-fos expression in specific brain areas and nociceptive behavior in trigeminal and extra-trigeminal body areas. Results URB602, a reversible MGL inhibitor, did not show any analgesic effect in the tail flick test, but it inhibited NTG-induced hyperalgesia in both the tail flick test and the formalin test applied to the hind paw or to the orofacial area. Quite unexpectedly, URB602 potentiated formalin-induced hyperalgesia in the trigeminal area when used alone. The latter result was also confirmed using a structurally distinct, irreversible MGL inhibitor, JZL184. URB602 did not induce neuronal activation in the area of interest, but significantly reduced the NTG-induced neuronal activation in the ventrolateral column of the periaqueductal grey and the nucleus trigeminalis caudalis. Conclusions These findings support the hypothesis that modulation of the endocannabinoid system may be a valuable approach for the treatment of migraine. The topographically segregated effect of MGL inhibition in trigeminal/extra-trigeminal areas calls for further mechanistic research.

scholarly journals A Short on Ubrogepant

2021 ◽  
pp. 79-81
Author(s):  
S. Padmaja ◽  
J. Mohan
Keyword(s):  
Receptor Antagonist ◽  
Research Process ◽  
Calcitonin Gene Related Peptide ◽  
Review Article ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Acute Attacks ◽  
Cgrp Receptor Antagonist

Migraine is a mysterious disorder characterized by pulsating head ache, which is actually characterized to one side and comes in attacks which will be lasting for about 3-48 hours and can be associated with nausea,vomiting,sensitivity to sound,flashes of light,vertigoand diarrhoea [1]. Most of the drugs which are in current use for actue migraine like triptans, treats the disorder symptomatically. A novel group of drugs has been in research for the migraine which treats the disorder pathologically. Calcitonin gene – related peptide (CGRP) has a major role in the pathophysiology of the disorder and hence CGRP receptor antagonist, known as Gepants are in the research process [2]. Gepants are being studied for the efficacy of treating acute migraine [2]. This article will be a review article about the drug – Ubrogepant, which is approved for treatment of migraine with acute attacks in adults [3].

scholarly journals Effect of Calcitonin Gene-Related Peptide Receptor Antagonists on Migraine Treatment: A Meta-Analysis

2021 ◽  
Author(s):  
Jiyoung Kim ◽  
Kyoungjune Pak ◽  
Gha-Hyun Lee ◽  
Jae Wook Cho ◽  
Hyun-Woo kim
Keyword(s):  
Meta Analysis ◽  
Calcitonin Gene Related Peptide ◽  
Migraine Treatment ◽  
Acute Migraine ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists ◽  
Acute Migraine Treatment

Abstract Background: The pathophysiology of migraine has been researched incessantly, and it has been suggested that calcitonin gene-related peptide (CGRP) is associated with migraine attacks. CGRP receptor blockers are attracting attention for migraine prevention and treatment of acute episodes, and CGRP receptor antagonists have been shown to be effective in treating acute migraine headaches. This meta-analysis aimed to assess the effect of available CGRP receptor antagonists, focusing on their therapeutic doses for acute migraine treatment.Methods: We performed a systematic search of MEDLINE (from inception to March 2021) and EMBASE (from inception to March 2021) for English publications using the keywords “migraine” and “Calcitonin gene-related peptide,” limited to human studies.Results: Five studies that focused on examining the effects of CGRP receptor antagonists on acute migraine treatment met the eligibility criteria for this meta-analysis. The pooled analysis demonstrated that the CGRP receptor antagonist improved freedom from pain (OR=2.066, 95% confidence interval [CI] 1.766–2.418, I2=0%), absence of bothersome symptoms (OR=1.606, 95% CI=1.408–1.830, I2=0%), pain relief (OR=1.791, 95% CI=1.598–2.008, I2=0%), and freedom from nausea (OR=1.361, 95% CI=1.196–1.548, I2=0%), significantly more than the placebo. Conclusions: CGRP receptor antagonists are effective for acute migraine treatment and are expected to be used clinically as emerging therapeutic agents.

Quinine analogs as non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists

1997 ◽  
Vol 7 (20) ◽  
pp. 2673-2676 ◽  
Author(s):  
Robert A. Daines ◽  
Kelvin K.C. Sham ◽  
Jack J. Taggart ◽  
William D. Kingsbury ◽  
James Chan ◽  
...  
Keyword(s):  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Receptor Antagonists ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonists

Zavegepant. Calcitonin gene-related peptide (CGRP) receptor antagonist, Treatment of migraine

2021 ◽  
Vol 46 (4) ◽  
pp. 281
Author(s):  
F. Cipolla ◽  
M. Capi ◽  
L. Lionetto ◽  
D. De Bernardini ◽  
V. De Angelis ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Calcitonin Gene Related Peptide ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonist

CGRP receptor antagonist olcegepant (BIBN4096BS) does not prevent glyceryl trinitrate-induced migraine

Cephalalgia ◽  
2010 ◽  
Vol 30 (11) ◽  
pp. 1346-1353 ◽  
Author(s):  
JF Tvedskov ◽  
P Tfelt-Hansen ◽  
KA Petersen ◽  
LT Jensen ◽  
J Olesen
Keyword(s):  
Glyceryl Trinitrate ◽  
Migraine Without Aura ◽  
Striking Similarity ◽  
Receptor Blockade ◽  
Cgrp Receptor ◽  
Double Blind ◽  
No Donor ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonist ◽  
No Releases

There is a striking similarity between the migraine-provoking effect of the nitric oxide (NO) donor glyceryl trinitrate (GTN) and that of calcitonin gene-related peptide (CGRP). We tested the hypothesis that NO releases CGRP to cause the delayed migraine attack after GTN. Methods: In a double-blind-cross-over study, 13 migraine without aura (MO) patients were administered GTN 0.5 µg/kg/minute for 20 minutes and subsequently BIBN4096BS (olcegepant) 10 mg or placebo. Headache scores and development of MO were followed for 24 hours. Results: MO developed in seven of 13 with olcegepant and in nine of 13 with placebo ( p = 0.68). The headache scores were similar after the two treatments ( p = 0.58). Thus CGRP receptor blockade did not prevent GTN-induced migraine. Conclusions: The present study indicates that NO does not induce migraine by liberating CGRP. The most likely explanation for our findings is that CGRP has its effect higher than NO in the cascade of events leading to MO attacks.

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