scholarly journals The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization but not cortical spreading depression-induced afferent sensitization

2017 ◽  
Author(s):  
Jun Zhao ◽  
Dan Levy
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Fold Increase ◽  
Male Rats ◽  
Cgrp Receptor ◽  
Unit Recording ◽  
Afferent Activation ◽  
Calcitonin Gene ◽  
Cgrp Receptor Antagonist ◽  
Afferent Response

AbstractIntroductionCortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of pro-inflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP).ObjectivesWe sought to investigate whether (i) a brief meningeal K+ stimulus leads to CGRP-dependent enhancement of meningeal afferent responses, and (ii) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling.MethodsExtracellular single-unit recording were used to record the activity of meningeal afferents in anesthetized male rats. Stimulations included a brief meningeal application of K+ or induction of CSD in the frontal cortex using pinprick. CSD was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. CGRP receptor activity was inhibited with BIBN4096 (333μM, i.v.).ResultsMeningeal K+ stimulation acutely activated 86% of the afferent tested and also promoted in ~65% of the afferents a 3-fold increase in ongoing activity which was delayed by 23.3±4.1 min and lasted for 22.2±5.6 min. K+ stimulation did not promote mechanical sensitization. Pretreatment with BIBN4096 suppressed the K+- induced delayed afferent activation, reduced CSD-evoked cortical hyperemia, but had no effect on the enhanced activation or mechanical sensitization of meningeal afferents following CSD.ConclusionWhile CGRP-mediated activation of meningeal afferents evoked by cortical efflux of K+ could promote headache, acute activation of CGRP receptors may not play a key role in mediating CSD-evoked headache.Previous presentation of the research, manuscript, or abstractParts of the manuscript have been presented previously only in an abstract form.

CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior

Cephalalgia ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 354-365 ◽  
Author(s):  
Aslı Filiz ◽  
Nermin Tepe ◽  
Sajedeh Eftekhari ◽  
H Evren Boran ◽  
Ergin Dilekoz ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Pain Behavior ◽  
Reticular Nucleus ◽  
Cgrp Receptor ◽  
Freely Moving Rats ◽  
Behavioral Studies ◽  
Freely Moving ◽  
Cgrp Receptor Antagonist

Background and objective The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. Methods CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. Results MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. Conclusion CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

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].

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.

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

Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits

1994 ◽  
Vol 266 (3) ◽  
pp. H1095-H1102 ◽  
Author(s):  
D. M. Colonna ◽  
W. Meng ◽  
D. D. Deal ◽  
D. W. Busija
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Topical Administration ◽  
Competitive Inhibitor ◽  
Calcitonin Gene Related Peptide ◽  
Cranial Window ◽  
Related Peptide ◽  
Brain Surface ◽  
Calcitonin Gene ◽  
Pial Arterioles

We examined the role of calcitonin gene-related peptide (CGRP) in cortical spreading depression (CSD)-induced dilation of rabbit pial arterioles. In urethan-anesthetized rabbits instrumented with a closed cranial window, CSD induction with KCl dilated pial arterioles from 86 +/- 10 to 132 +/- 13 (mean +/- SE, n = 6) microns (a 54 +/- 9% increase). Topical administration of 12.8 microM CGRP-(8-37), a competitive inhibitor of the CGRP receptor, reduced CSD-induced pial dilation from 54 +/- 9% baseline to 33 +/- 9% (P < 0.05). Removal of the receptor antagonist from the brain surface restored CSD-induced dilation to 59 +/- 11% (P < 0.05, compared with the response with the antagonist present). In other animals, we showed that this dose of the CGRP antagonist attenuated arteriolar dilation to topically applied 10(-7) M CGRP (n = 5), but it did not alter arteriolar dilation to arterial hypercapnia. We also evaluated the dilator potency of substance P (SP) compared with CGRP. Dilation with 10(-7) M SP was only 22 +/- 11%, whereas arterioles dilated to 57 +/- 7% above baseline diameter with 10(-7) M CGRP. We conclude that CGRP contributes to the transient arteriolar dilation that is characteristic of CSD.

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.

Cortical Spreading Depression Does Not Result in the Release of Calcitonin Gene-Related Peptide into the External Jugular Vein of the Cat: Relevance to Human Migraine

Cephalalgia ◽  
1993 ◽  
Vol 13 (3) ◽  
pp. 180-183 ◽  
Author(s):  
Richard D Piper ◽  
Lars Edvinsson ◽  
Rolf Ekman ◽  
Geoffrey A Lambert
Keyword(s):  
Migraine With Aura ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Jugular Vein ◽  
Calcitonin Gene Related Peptide ◽  
External Jugular Vein ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Vasoactive Peptide ◽  
Stimulation Of

There is circumstantial evidence that cortical spreading depression (SD) may account for the scotoma and the “spreading cortical oligemia” seen during migraine with aura. It has been shown that calcitonin gene-related peptide (CGRP) is increased in blood taken from the external jugular vein (EJV) in humans during migraine and after stimulation of the trigeminal ganglion. To test the hypothesis that cortical SD may elevate the concentration of this vasoactive peptide in the EJV during migraine, we have measured its concentration in the external jugular vein of cats during cortical SD. This study demonstrates that SD has no effect on the concentration of CGRP either during the passage of a wave of spreading depression across the cortex or, 60 min later, during the period of post-SD cortical oligemia.

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