Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain

1 The therapeutical bene®t of serotonin (5-HT 1 ) receptor agonists in the treatment of migraine headache has been attributed to their inhibitory e ect on the release of pro-in¯ammatory neuropeptides from trigeminal a erents within the cranial meninges. The e ect of 5-HT 1 receptor agonists on the release of neuropeptides from central a erent terminals has not been examined so far. In the present study in the rat we therefore measured the e ect of the 5-HT 1B receptor agonist CP 93,129 on the stimulation-evoked release of immunoreactive substance P (ir-SP) in the spinal trigeminal nucleus. 2 To measure release of ir-SP, microprobes coated with antibody to substance P were inserted into the medulla oblongata at the level of the obex. The ipsilateral parietal dura mater encephali was exposed and stimulated with acid phosphate bu ered Tyrode solution (pH 5.8). This chemical stimulus increased the release of ir-SP in the medullary dorsal horn. 3 Systemic (i.v.) administration of CP 93,129 (460 nmol kg 71 ) prior to stimulation suppressed the stimulation-evoked increase of release of ir-SP. Local administration of CP 93,129 (10 mM) to the dorsal surface of the medulla had no signi®cant inhibitory e ect on the release. 4 It is concluded that systemically applied 5-HT 1 receptor agonists reduce the stimulation-evoked release of substance P from the central endings of meningeal a erents in the spinal trigeminal nucleus (medullary dorsal horn). This inhibitory e ect may contribute to the antinociceptive e ect of 5-HT 1 receptor agonists in migraine.

Section: Discussionmentioning

confidence: 83%

Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH – inhibition by the serotonin (5‐HT₁) receptor agonist CP 93,129

Meßlinger¹,

Ebersberger²,

Schaible³

1998

“…The skull was then opened, the brain removed and the cranial cavity thoroughly rinsed with saline. Dura mater was dissected bilaterally as previously described (Markowitz et al, 1987). The large dural sinuses, the region of dura through which the electrodes penetrated, and the dura covering the trigeminal ganglion were excluded from analysis.…”

Section: Introductionmentioning

confidence: 99%

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

Buzzi

Moskowitz

Peroutka

et al. 1991

102

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, ...

“…5-HT1 receptors mediate inhibition of plasma leakage within rat dura mater following trigeminal electrical stimulation (Buzzi et al, 1991b (Markowitz et al, 1987; and radioactivity determined on the two sides.…”

mentioning

confidence: 99%

CP‐93,129, a potent and selective 5‐HT_1B receptor agonist blocks neurogenic plasma extravasation within rat but not guinea‐pig dura mater

Matsubara

Moskowitz

Byun

1991

Pretreatment with CP-93,129 blocked plasma extravasation in rat dura mater induced by electrical trigeminal ganglion stimulation when administered at > 140 nmol kg-1, i.v. but did not affect plasma leakage in guinea-pig at 460 or 1400nmolkg-'. Sumatriptan, a 5-HTlD-like receptor agonist, blocked plasma extravasation in the guinea-pig model when administered at 7 nmol kg '. In as much as CP-93,129 binds with micromolar affinities to 5-HT1A, 5-HT1c, 5-HTlD, and 5-HT2 recognition sites, and with nanomolar affinity to the 5-HT1B receptor subtype, blockade of plasma extravasation in the rat dura mater may be mediated by 5-HTlB receptors whereas the 5-HTlD receptor may be more relevant to the guinea-pig.