Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg−1), naproxen (30 mg kg−1) and ibuprofen (30 mg kg−1) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are probably among the most widely used analgesics used to treat headache, including many of the primary headache disorders
Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua
The data demonstrate indomethacin, naproxen and ibuprofen are able to inhibit dural vasodilation induced by electrical stimulation, with ibuprofen showing a later onset of the inhibition, and indomethacin a shorter duration of the effect when compared to the two other drugs used
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are probably among the most widely used analgesics used to treat headache, including many of the primary headache disorders. Where they are the first line treatment for acute attacks, they offer the most cost effective treatment showing only minor side effects [1]. These substances have been used clinically for many years, and it is known that they share mechanisms that involve inhibition of the different cyclooxygenases (COX) [2, 3], it is not clear which mechanisms, apart from the known COX-1/-2 inhibition, defines their different clinical profiles relevant for the treatment of headaches. By testing the effect of various intracisternally administered COX inhibitors, including indomethacin, on trigeminal ganglion
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