4991W93, a potent blocker of neurogenic plasma protein extravasation, inhibits trigeminal neurons at 5-hydroxytryptamine (5-MT1B/1D) agonist doses

Triptans share the pharmacological profile of being 5-hydroxytryptamine (5- HT1B/1D) agonists and having potent anti-migraine activity. The conformatio nally restricted zolmitriptan analogue 4991W93 was developed as a potent, a nd at low doses, specific, non-vasconstrictor inhibitor of neurogenic dural plasma protein extravasation. Here, we sought to study the effect of 4991W 93 at plasma protein extravasation blocking and at 5-HT1B/1D agonist doses. Nociceptive cells with firing latencies consistent with A delta fibres wer e recorded in the dorsal horn region of the trigeminal nucleus caudalis aft er electrical stimulation of the sagittal sinus. Both evoked (13 units) and free running (6 units) activity in cells linked to sagittal sinus stimulat ion were inhibited by 4991W93 delivered microiontophoretically or by intrav enous administration at 10 mug/kg or 100 mug/kg, but not 0.1 mug/kg. When a pplied iontophoretically, 4991W93 did not appear to have an additive effect over a 5-HT1B/1D agonist effective concentration of zolmitriptan. These da ta suggest that 4991W93 is only effective at modulating the trigeminocervic al complex at 5-HT1B/1D agonist doses. To account for neurogenic dural plas ma protein extravasation blockade in animal studies. 4991W93 might have non -5-HT1B/1D-based pharmacological targets that are yet to be described. (C) 2001 Elsevier Science Ltd. All rights reserved.