Background: 

Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. aCGRP is prominently localized in primary afferent C and Ad fibres of spinal and trigeminal ganglia, verified by selective antidromic tracing.

Purpose: 

We have shown that the activation of the trigeminovascular pathway results in the release of CGRP both in animal and man. The trigeminal nerve activation results in antidromic release of CGRP, acting via the CGRP receptor, which is located both in intracranial vessels and in the trigeminal nuclear complex in the brain stem. CGRP receptors are localized in the vascular smooth muscle cells, both in meningeal and cerebral arteries; antagonists that reduce signaling in the trigeminovascular pathway putatively act at multiple sites inside the blood-brain barrier. Here we will discuss recent developments in our understanding of the role of CGRP and its receptor in the cranial circulation related to migraine. A central question is "where do the new CGRP antagonists act?"(1).

Recent results: 

In the trigeminal ganglion we have found that there is a close association between satellite glial cells (SGC) and the neurons, storing CGRP and other neuronal messengers. In a model of inflammation the expression is enhanced in the neurons but the SGC show the capacity to form CGRP; there are CGRP receptor elements RAMP1 and CLR expressed in both. This may suggest intraganglionic signaling. The tracing studies often end in the TNC, here we have applied a CNS tracer and found that the projections reach both the PAG and the thalamus.

The recent development in therapy is the specific CGRP receptor blockers olcegepant and telcagepant; these have added important information on the role of CGRP in migraine as well as indicating the site of antimigraine target. Another ways of interacting with CGRP mechanisms have appeared; limiting the availability of CGRP in the circulation with a specific CGRP antibody or a CGRP-binding RNA-Spiegelmer. Either way reduces neurogenic inflammation and attenuates signaling within the trigeminovascular pathway, however, they are limited in effect by the blood-brain barrier. Specific CGRP receptor blockade has been shown to reduce the effect of released CGRP and to abort acute migraine attacks (2).

Conclusions: 

Although the triptans produce relief for many people, a substantial number of affected individuals are unsuited due to cardiovascular co-morbidity or simply not responding to these compounds. The new class of antimigraine drugs may provide some hope of relief.

References 

[1] Edvinsson L. CGRP blockers in migraine therapy: where do they act? Br J Pharmacol. 155:967–969, 2008

[2] Edvinsson L. CGRP-receptor antagonism in migraine treatment. Lancet. 372:2089–2090, 2008