Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF

Hoffmann, J.; Wecker, Sascha; Neeb, Lars; Dirnagl, Ulrich; Reuter, Uwe

doi:10.1177/0333102412447701

Cited by 50 publications

(43 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…, ). In fact, CGRP in the peripheral circulation, due to activation of the trigeminovascular system, is principally released from the TG (Hoffmann et al ., ). Primary cultured TG neurons have been shown to express functional CGRP receptors (Zhang et al .…”

Section: Cgrp and Receptor Localization In The Trigeminovascular Systmentioning

confidence: 97%

“…Stimulation of the TG by capsaicin, KCl or electrical impulse, results in the release of CGRP (Goadsby et al, 1988;Capuano et al, 2007). In fact, CGRP in the peripheral circulation, due to activation of the trigeminovascular system, is principally released from the TG (Hoffmann et al, 2012). Primary cultured TG neurons have been shown to express functional CGRP receptors (Zhang et al, 2007).…”

Section: Cgrp and Receptor Localization In The Trigeminovascular Systmentioning

confidence: 99%

See 1 more Smart Citation

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

Walker

Hay

2013

British J Pharmacology

View full text Add to dashboard Cite

The neuropeptide calcitonin gene-related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the trigeminovascular system. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor-like receptor (CLR). This associates with receptor activity-modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type-dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the trigeminovascular system. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this system and that further work is required to determine their contribution to CGRP physiology and pathophysiology. LINKED ARTICLES

show abstract

Section: Cgrp and Receptor Localization In The Trigeminovascular Systmentioning

confidence: 97%

Section: Cgrp and Receptor Localization In The Trigeminovascular Systmentioning

confidence: 99%

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

Walker

Hay

2013

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…A recent systematic review and meta‐analysis of migraine biomarkers has shown that CGRP in CSF and blood was elevated in chronic migraine patients (glutamate and NGF were also increased), and levels of the endogenous opiate β‐endorphin decreased . Preclinically, it has been shown that cortical spreading depolarization/depression (CSD) may trigger the release of neuropeptides such as CGRP into the jugular vein and CSF from the primary trigeminal afferent fibers, where it could promote sensitization of the trigeminal system. In contrast, there are findings that suggest that acute activation of CGRP receptors may not play a key role in mediating CSD‐evoked headache, but CGRP‐mediated activation of meningeal afferents evoked by cortical efflux of potassium ion could promote headache.…”

Section: Questions To Ponder?mentioning

confidence: 99%

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

2019

View full text Add to dashboard Cite

Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain‐producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP‐RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo‐controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11C]MK‐4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP‐RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP‐RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood‐brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next‐generation small molecule CGRP‐RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP‐based therapeutic options for migraine patients.

show abstract

“…Trigeminal CGRP, through its roles in vasodilation, neurogenic inflammation, and peripheral sensitization, is likely to contribute to the most relevant peripheral actions in migraine . The main source of CGRP in migraine is primary trigeminal afferents, as plasma‐derived CGRP is unlikely to reach the ventroposterior medial thalamic nucleus because of poor penetration of the BBB . In the periphery, afferent endings of sensory neurons innervate blood vessels in almost every organ system, but the implications of CGRP release here in relation to migraine are unclear …”

Section: Expression and Functional Role Of Cgrp And Cgrp Receptors Inmentioning

confidence: 99%

The CGRP Pathway in Migraine as a Viable Target for Therapies

Edvinsson

2018

Headache

View full text Add to dashboard Cite

The neuropeptide calcitonin gene-related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene-related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene-related peptide in the central and peripheral nervous system. Of these, the calcitonin gene-related peptide receptor, which binds calcitonin gene-related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies. An incentive to pursue such research is the continuing unmet medical need of patients. Triptans have offered some clinical benefit, but many patients do not respond and these drugs have important safety considerations. Initial calcitonin gene-related peptide-focused research led to development of the "gepant" small-molecule calcitonin gene-related peptide receptor blockers. Positive efficacy reports concerning the gepants have been tempered by safety findings which led to the discontinuation of some of these agents. Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long-term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies.

show abstract

Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF

Abstract: We conclude that resting state CGRP levels can be maintained after trigeminal denervation of the meninges. However, for functional purposes primary trigeminal afferents are mandatory as they are the major source for stimulus-induced CGRP release.

Cited by 50 publications

References 37 publications

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

The CGRP Pathway in Migraine as a Viable Target for Therapies

Contact Info

Product

Resources

About