Time‐dependent blockade of neurogenic plasma extravasation in dura mater by 5‐HT_1B/D agonists and endopeptidase 24.11

Abstract

1 The delayed effects of stimulating the trigeminal ganglion unilaterally in rats and guinea-pigs were assessed by measuring the leakage of radiolabelled albumin from blood into the dura mater at intervals for up to 120 min after a 5 min stimulation period (5 Hz, 0.6 mA, 5 ms).2 ['25I]-albumin (50 iCi kg-') was injected i.v. as a tracer 0, 20, 50, 80 or 110 min after stimulation and the animals were killed 10 min later. Extravasation of plasma protein developed for up to 90 min poststimulation. 3 To examine the mechanism underlying delayed plasma protein extravasation, CP-93,129 (5-HTB receptor agonist, 460nmolkg-'), sumatriptan (5-HTBX receptor agonist, 24nmolkg-'), or neutral endopeptidase 24.11 (1 nmol kg-') were administered 45 or 75 min after trigeminal stimulation and 5 min before radiolabelled albumin. The extravasation response was reduced at 45 min. CP-23,129 also blocked extravasation when injected 25 min after capsaicin administration (1 11mol kg-').4 If the tracer was injected 5 min prior to electrical trigeminal stimulation, endopeptidase 24.11 (1 nmol kg-') given 10 min before stimulation blocked the leakage (as reported previously for CP-93,129 or sumatriptan). All three compounds blocked the leakage when administered 30 min (but not 60 min) poststimulation in this paradigm. 5 The data support the previously made contention that neuropeptide release from sensory fibres mediates the plasma extravasation response following trigeminal ganglion stimulation, and that release and plasma leakage continue many minutes beyond the stimulation period. Hence, drugs that inhibit neuropeptide release (CP-93,129, sumatriptan), or enhance breakdown of neuropeptide mediators (endopeptidase 24.11) block the delayed extravasation response. Extravasation developing later than 45 min poststimulation was not neurogenically mediated.

The in vivo pharmacological profile of a 5‐HT1 receptor agonist, CP‐122, 288, a selective inhibitor of neurogenic inflammation

“…These data are consistent with the ability of sumatripan to contract preparations of human isolated saphenous vein (Bax et al, 1992) and coronary artery (Connor et al, 1989;Cocks et al, 1993;Kaumann et al, 1994). In fact, cardiovascular side-effects have been reported in response to sumatripan (Willett et al, 1992;Ottervanger et al, 1993) (Huang et al, 1993). The processes which are responsible for this continued release of neuropeptides have not been examined; however, this experimental protocol provided a simple and convenient method of demonstrating that sumatriptan and endopeptidase 24,11 could reverse an established and ongoing neurogenically-driven sterile inflammation within minutes when administered during this period of continual neuronal firing (Huang et al, 1993).…”

“…By use of the original protocol to evaluate inhibitors of neurogenic inflammation, when compound is administered prior to stimulation of the trigeminal ganglion, it is not possible to deduce whether an established and ongoing inflammation could be inhibited rapidly by the prejunctional inhibition of peptide release. However, following a brief period of electrical stimulation of the trigeminal ganglion (5 min), Moskowitz and co-workers have demonstrated that a period of neurogenically-driven plasma protein extravasation from the dural vasculature remains for up to 45 min (Huang et al, 1993). Thus, under these modified experimental conditions, CP-122,288 (present study) and sumatriptan (Huang et al, 1993) produced an immediate and effective inhibition of plasma protein leakage.…”

“…However, following a brief period of electrical stimulation of the trigeminal ganglion (5 min), Moskowitz and co-workers have demonstrated that a period of neurogenically-driven plasma protein extravasation from the dural vasculature remains for up to 45 min (Huang et al, 1993). Thus, under these modified experimental conditions, CP-122,288 (present study) and sumatriptan (Huang et al, 1993) produced an immediate and effective inhibition of plasma protein leakage. Importantly, the administration of compound during a period of continual firing of the trigeminal nerve did not reduce the ability of low ng kg-' doses of CP-122,288 to inhibit plasma protein leakage.…”

“…In fact, cardiovascular side-effects have been reported in response to sumatripan (Willett et al, 1992;Ottervanger et al, 1993) (Huang et al, 1993). The processes which are responsible for this continued release of neuropeptides have not been examined; however, this experimental protocol provided a simple and convenient method of demonstrating that sumatriptan and endopeptidase 24,11 could reverse an established and ongoing neurogenically-driven sterile inflammation within minutes when administered during this period of continual neuronal firing (Huang et al, 1993). Thus, if the inflammatory environment that develops using this experimental protocol mimics those events which occur pathophysiologically during migraine, then it appears that the inflammatory process could be inhibited by a prejunctional inhibition of peptide release within a clinically relevant timescale.…”

“…The aims of the work described in this paper were as follows:-(i) since differences in pharmacology are frequently observed between different animal species, the ability of CP-122,288 to inhibit intracranial neurogenic inflammation in a second animal species, rat, was examined; (ii) to investigate the ability of CP-122,288 to reverse an established and ongoing neurogenic inflammation using the method of Huang et al (1993), and (iii) to define the dose-range over which 288 produced haemodynamic and vasoconstrictor effects in the anaesthetized dog, a species which has been of use, unlike rat (Spokes & Middlefell, 1993), for investigating the contractile activity of compounds mediated via activation of vascular '5-HTID-like' receptors In a separate series of experiments using rats anaesthetized with Inactin (120 mg ml-' solution in 0.9% saline; 0.1 ml 100 g-' body weight i.p. ), arterial blood pressure was recorded via the femoral artery with a Gould pressure transducer (model P231D).…”