Further characterization of the putative 5‐HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater

1 We describe the effects of pretreatment with 5‐hydroxytryptamine (5‐HT) receptor agonists and antagonists on neurogenically‐mediated plasma protein extravasation ([ 125 I]‐albumin) in rat dura mater and in extracranial tissues (temporalis muscle fascia, conjunctiva, eyelid and lip) induced by electrical stimulation of the right trigeminal ganglion. 2 Leakage of [ 125 I]‐bovine serum albumin from blood vessels in dura mater following high intensity stimulation (1.2 mA, 5 ms, 5 Hz for 5 min) was significantly reduced by the intravenous administration of drugs active at 5‐HT receptors with some selectivity for the 5‐HT 1 receptor subtypes: 5‐carboxamidotryptamine (5‐CT) (threshold dose, 1 ng kg −1 ); 5‐benzyloxytryptamine (5‐BT) (10, 30 or 100 μg kg −1 ); 8‐hydroxydipropylaminotetralin (8‐OH‐DPAT) (300 μg kg −1 ); and as previously reported, sumatriptan (100 μg kg −1 ), dihydroergotamine (DHE) (50 μg kg −1 ), ergotamine tartrate (100 μg kg −1 ) and chronically administered methysergide (1 mg kg −1 ). 3 The putative 5‐HT receptor antagonist, metergoline 100 μg kg −1 , inhibited partially the effect of sumatriptan in dura mater providing additional evidence for a 5‐HT 1 receptor subtype‐mediated mechanism, although it was not effective against 5‐CT (1 ng kg −1 ). Methiothepin (300 μg kg −1 ) did not affect the response to sumatriptan. When administered at high concentrations (1 mg kg −1 ) methiothepin and metergoline decreased plasma protein extravasation in rat dura mater. 4 Pretreatment with the 5‐HT 2 receptor antagonists pizotifen, 300 μg kg −1 , or ketanserin, 300 μg kg −1 , or the 5‐HT 3 receptor antagonists MDL 72222, 300 μg kg −1 , or ICS 205–930, 300 μg kg −1 , did not affect plasma protein leakage following electrical trigeminal stimulation. Blockade by sumatriptan of plasma protein extravasation was not inhibited by pizotifen (300 μg kg −1 ) or MDL 72222 (300 μgkg −1 ). 5 The 5‐HT receptor(s) mediating this response were present only on intracranial tissues innervated by the trigeminal nerve; plasma protein extravasation in extracranial tissues was not blocked by pretreatment with the equivalent or higher concentrations of the above drugs following low intensity trigeminal stimulation (0.1 mA, 5 ms, 5 Hz). 6 The putative 5‐HT receptor(s) mediating this response were not present on sympathetic fibres innervating dura mater since unilateral removal of the superior cervical ganglion did not prevent the development of plasma protein extravasation nor did it affect the blockade by sumatriptan 100 μg kg −1 . 7 The above pharmacological data suggest that intracranial vessels possess 5‐HT receptor(s) which are coupled to inhibition of neurogenically‐mediated plasma protein extravasation. These receptors cannot be detected on extracranial cephalic blood vessels innervated by the trigeminal nerve, although available evidence strongly suggests that the 5‐HT receptors reside on perivascular trigeminal nerve fibres. The rank order of effective doses (threshold concentrations; 5‐CT < 5‐BT < DHE < sumatriptan < 8‐OHDPAT) is most consistent with a 5‐HT 1B ‐ or 5‐HT 1D ‐mediated response, among the known 5‐HT 1 family of receptors. However, the lack of effect of methiothepin against the actions of sumatriptan, or metergoline against the effects of 5‐CT suggest important differences and the possibility that a previously unrecognized 5‐HT receptor(s) is involved in this response.