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2010 MRF Research Grantee
FINAL REPORT: Mechanisms of Blood Brain Barrier Dysfunction Induced Medication Overuse Headache
Triptan medication is often used in chronic migraine therapy. However, it appears that prolonged frequent triptan use may induce headache, a condition termed “medication overuse headache” (MOH). The mechanisms that underlie MOH are not fully understood, but may be induced by periods of absence of medication. In this study we hypothesized that prolonged triptan medication induces changes in the blood brain barrier (BBB). This change in BBB integrity provides the stimuli that activate pain-signaling pathways and provoke migraine attack selectively in migraineurs. An intact BBB is critical in maintaining brain homeostasis.
To test our hypothesis, we infused rats with either saline or sumatriptan for 7 days. We then administered an intraperitoneal injection of either saline or sumatriptan antagonist to pharmacologically induce triptan medication withdrawal. Changes in BBB integrity were assessed in the trigeminal nucleus caudalis brain region, an area involved in the transmission of headache pain.
Results show that animals dosed with saline for 7 days and injected with either saline or the sumatriptan antagonist for 6 hours had no effect on BBB integrity. However, animals dosed with sumatriptan for 7 days and with either saline or the sumatriptan antagonist for 6 hours showed a loss of vascular integrity typically associated with loss of BBB integrity.
Hypothesis vs. Findings
The results confirmed and validated the original hypothesis.
We show that triptan-based medication modulates BBB integrity. However, the mechanism of this modulation remains unclear. Triptans may act directly on the vascular endothelial cells or on other components of the neurovascular unit. To address this question we have started using endothelial and astrocytic cultures. Preliminary studies show that both these cell types express 5HT1B/D receptors. Thus, sumatriptan potentially acts on both cell types at the neurovascular unit. Our ongoing in vitro research may provide insight into the intracellular signaling mechanisms that induce changes in tight junction protein expression.
A further potentially very important observation is that in in vivo following sumatriptan administration, there appeared to be a change in astrocyte morphology. In other studies, we have previously shown that astrocytes play a critical role in maintaining BBB integrity. Therefore this line of research will be continued. If these further studies support the initial observation, this will represent a major advance in understanding the mechanisms leading to MOH.
What This Research Means to You
Results from this study suggest that triptan-based medication modulates the integrity of the BBB. A greater understanding of how alterations in BBB integrity may increase the probability of MOH will give insight into the underlying pathology of migraine. This study provides novel therapeutic avenues for migraine suffers aimed at maintaining BBB integrity.