ABSTRACT

The present PhD dissertation derives from the Danish Headache Center and concerns the role of cyclic adenosine monophosphate (cAMP) in the pathogenesis of migraine headache.

For research tools, we used adenosine, whose vasodilator and pro-nociceptive actions are mediated by increases in cAMP; and cilostazol, a drug that attenuates cAMP hydrolysis by inhibiting phosphodiesterase type 3 (PDE3). These substances were administered to healthy volunteers in a double-blind, crossover design. Headache response was studied with a verbal rating scale. Regional cerebral blood flow was measured using 133 Xe inhalation and SPECT and middle cerebral artery (MCA) blood flow velocity measured with transcranial Doppler. Obtaining these values in direct sequence allowed assessment of MCA diameter changes. Mechanical pain thresholds were measured in a region innervated by the 1st division of the trigeminal nerve (cilostazol study only).

In addition to the clinical studies, in vitro pharmacology was used to assess the mechanism involved in the relaxant response to cilostazol.

The in vitro studies confirmed that PDE3 plays a major role in cAMP hydrolysis in cerebral arteries. Functionally, cilostazol dilated pre-contracted guinea pig basilar arteries with a concomitant increase in cAMP. Due to methodological limitations a clear relationship between cAMP and relaxant response could, however, not be established.

Cilostazol 200 mg p.o. induced headache in 11 of 12 volunteers compared to two after placebo. The pain quality associated with the headache often had migraine-like features and two of completed volunteers developed attacks fulfilling criteria for migraine without aura. Cilostazol significantly increased MCA diameter. No changes in mechanical pain thresholds could be detected.

Adenosine was tested using 80 μ g × kg -1 × min -1 and 120 μ g × kg -1 × min -1 vs. placebo. There was an overall significant increase in headache score between treatments, but the headache was very mild. MCA diameter remained unchanged. The most likely explanation is that adenosine cannot pass the blood-brain barrier. We found little evidence for circulating adenosine playing a role in spontaneous migraine attacks as previously proposed.

These findings support a role of cAMP in migraine pathogenesis. The mechanism involved may be dilatation of large cerebral arteries. Peripheral or central sensitisation of trigeminal afferents has also been suggested as a possible mechanism. We found no results supporting this, but the study was not primarily designed to investigate this. Further investigations of the role of cAMP in migraine and the molecular and functional downstream mechanisms involved seem warranted in the search of future anti-migraine molecular targets.