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

Abstract

1 We describe the effects of pretreatment with 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on neurogenically-mediated plasma protein extravasation (["25I]-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 [25I]-bovine serum albumin from blood vessels in dura mater following high intensity stimulation (1.2 mA, Sims, 5Hz for 5min) was significantly reduced by the intravenous administration of drugs active at 5-HT receptors with some selectivity for the 5-HT1 receptor subtypes: 5-carboxamidotryptamine (5-CT) (threshold dose, 1ngkg-1); 5-benzyloxytryptamine (5-BT) (10, 30 or 100augkg-1); 8-hydroxydipropylaminotetralin (8-OH-DPAT) (300pigkg-1); and as previously reported, sumatriptan (lOOpugkg -), dihydroergotamine (DHE) (SOugkg 1), ergotamine tartrate (lOO1ugkg 1) and chronically administered methysergide (1 mgkg-1).3 The putative 5-HT receptor antagonist, metergoline lOOpgkg-1, inhibited partially the effect of sumatriptan in dura mater providing additional evidence for a 5-HT1 receptor subtype-mediated mechanism, although it was not effective against 5-CT (1 ng kg-1). Methiothepin (300,ug 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-HT2 receptor antagonists pizotifen, 300pugkg 1, or ketanserin, 300,ugkg ', or the 5-HT3 receptor antagonists MDL 72222, 300,ugkg-1, or ICS 205-930, 300pgkg-1, did not affect plasma protein leakage following electrical trigeminal stimulation. Blockade by sumatriptan of plasma protein extravasation was not inhibited by pizotifen (300,ug kg-1) or MDL 72222 (300pg kg-').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 IOOpug kg-'. 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-HTlB-or 5-HTlD-mediated response, ...

Neuropeptide release from slices of rat and guinea pig trigeminal ganglia: modulation by dihydroergotamine and sumatriptan

“…Dihydroergotamine is far from being a selective drug, and it shares with ergotamine the ability to stimulate α-adrenoceptors, dopamine receptors and 5-HT receptors [24]. Among this pleiotropic range of actions, it may also bind with high affinity and stimulate 5-HT 1B/D receptor subtypes [13,25]. In contrast sumatriptan, the first successful compound of this expanding class of antimigraine drugs, has a rather discriminating spectrum of action, because it stimulates selectively 5-HT 1B/D receptors [1].…”

Interpreting Vessel Diameter Changes in Vascular Headaches

“…Because blood in the subarachnoid space causes severe headache and is associated with intense vasoconstriction, the data suggest that constriction of dilated vessels is not the relevant prerequisite for 5-HT 1 -induced analgesia in vascular headaches. In fact, recent data suggest that the 5-HT 1 receptor subtype mediating contraction of vascular smooth muscle may not be identical to the receptor which blocks neural transmission within trigemino-vascular neurons (15). If true, it may be possible in the future to dissociate the two effects and to develop drugs which possess the analgesic effects only.…”

“…Assuming that vasoconstriction is important, one untested speculation holds that vasoconstriction might alter the geometry of perivascular fibers and, by so doing, affect the pain threshold. Another suggests that vasoconstriction may change transmural pressure in such a way as to reduce impulse traffic from sensitized vessels (6,8,14,15). While these ideas await experimental scrutiny, Friberg, Dahl and their colleagues have provided an important new clinical direction and new tools with which to address relevant clinical questions.…”

“…Might inhibition of neuropeptide release and blockade of peptide-mediated vasodilatation underlie the drug-induced vessel narrowing? Recently, we observed two neuronally mediated actions of sumatriptan and related drugs which might explain the changes in vessel caliber and analgesia (8,(14)(15)(16). We reported that sumatriptan and the ergot alkaloids (i.e.…”

Blockade by oral or parenteral RPR 100893 (a non‐peptide NK1 receptor antagonist) of neurogenic plasma protein extravasation within guinea‐pig dura mater and conjunctiva

“…Drugs useful for the treatment of acute migraine block NI within the dura mater. For example, sumatriptan or dihydroergotamine activate prejunctional 5-HT1D/B heteroreceptors and block the development of NI by inhibiting neuropeptide release from trigeminovascular fibres (Buzzi et al, 1991).…”