Clinical and Preclinical Rationale for CGRP-Receptor Antagonists in the Treatment of Migraine

Stewart J. Tepper, MD; Mark J. Stillman, MD


Headache. 2008;48(8):1259-1268. 

In This Article

Further Evidence for CGRP in Animal Models and Migraine

Using an in vitro trigeminal ganglion neuronal model, Durham and Russo reported a large increase in CGRP release when neurons were exposed to KCl, and exposure to capsaicin, which stimulates trigeminal sensory fibers, also caused marked CGRP release. The group then dosed the neurons with an inflammatory cocktail, in an attempt to mimic neurogenic inflammation, which resulted in augmented CGRP release, at least as large as that produced by KCl or capsaicin. These researchers concluded that trigeminal ganglia neuronal release of CGRP under conditions mimicking neurogenic inflammation is consistent with a role for CGRP in migraine. In a third part to the experiment, Durham and Russo reported that after trigeminal sensory neurons were stimulated with KCl or inflammatory cocktail, sumatriptan inhibited the release of CGRP, providing a link to migraine treatment.[4,30]

Gallai etal measured ictal and interictal levels of CGRP in the plasma of 30 young migraine patients with aura (MA) and 45 migraine patients without aura (MO) and compared the results with those of 30 age-matched controls. An elevation of CGRP levels in plasma was found during attacks in MA and, to a lesser extent, in MO (P<.03 and P<.05, respectively), once again suggesting a role for CGRP in migraine attacks, at least in juvenile migraine patients.[31]

Lassen etal described the effect of injecting CGRP into humans in a double-blind, placebo-controlled, crossover study. Intravenous CGRP was given to 10 migraine patients over 20 minutes and caused headache in virtually all migraine sufferers, whereas placebo did not. The headache occurred during the infusion and disappeared or diminished after infusion stopped. After a median of 5 hours, there was a delayed, stronger headache, with most of the characteristics of migraine in 9 subjects, while the headaches in 3 met strict IHS criteria for MO. CGRP appeared to have caused migraine-like headaches in a delayed fashion in these migraineurs.[32] Furthermore, IV CGRP caused only mild, non-migraine headache in non-migraineurs.[33]

In a very similar fashion, migraineurs treated with nitroglycerin (NTG) also develop an initial headache and then a delayed headache meeting criteria for MO. Juhasz and colleagues studied 15 women with MO and 8 controls administered 0.5mg of sublingual NTG. Plasma CGRP concentrations did not change during the immediate headaches and in the subjects without delayed migraine attacks. Plasma CGRP concentration increased significantly (P<.01) during the delayed migraine attacks and returned to baseline after the attacks stopped. In addition, both the change and peaks showed significant positive correlations with migraine headache intensity (P<.001).[34]

The synthesis of CGRP involves a complex CGRP promoter with multiple sites that regulate and enhance the process. For example, nerve growth factor (NGF) has been shown to stimulate CGRP synthesis by activating enhancer elements. Durham and Russo demonstrated that sumatriptan suppressed NGF- and MAPK-stimulated CGRP promoter activity in rat trigeminal ganglion culture, suggesting multiple sites of action for triptans in preventing CGRP effects in models for migraine processes.[30] Adding to these in vitro data, Durham and colleagues used recombinant adenovirus containing rat CGRP promoter to demonstrate CGRP-expressing neurons. Promoter activity was decreased by sumatriptan, eletriptan, and rizatriptan (see figure below [figure3]).[4,35]

Figure 3.

CGRP regulation in trigeminal ganglia neurons.[14]

Investigating the potential role of botulinum neurotoxin, type A in preventing chronic daily headache or frequent episodic migraine,[36,37] Durham and colleagues demonstrated that botulinum neurotoxin type A inhibited release of CGRP from rat trigeminal cultures stimulated with KCl or capsaicin. They speculated that the possible prophylactic efficacy of botulinum toxin type A, like the acute efficacy of triptans, may be partly attributed to the toxin's inhibitory effect on release of CGRP from trigeminal neurons.[38]

Zhang and colleagues demonstrated that activation of CGRP receptors on cultured trigeminal ganglion neurons increased CGRP mRNA levels and CGRP promoter activity. The promoter activation was cAMP dependent, and gene transfer using an adenoviral hRAMP1 expression vector increased production of cAMP. To establish whether RAMP1 was limiting in vivo, a transgenic mouse expressing hRAMP1 in the nervous system was generated. After CGRP injection into the whisker pad, the hRAMP1 transgenic mice displayed 2.2-fold greater plasma extravasation, a measure of neurogenic inflammation. The authors speculated that, as the rate-limiting step for CGRP receptor activity in trigeminal neurons, elevated RAMP1 activity might sensitize susceptible migrainous individuals to the action of CGRP.[39]


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