Troels Wienecke

PACAP38 induces migraine-like attacks in patients with migraine without aura

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

Prostaglandin E2 (PGE2) Induces Headache in Healthy Subjects

The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E2 (PGE2) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE2 might induce headache and vasodilation of cranial vessels. PGE2 (0.40 μg kg−1 min−1) or saline was infused for 25 min into 11 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (VMCA) by transcranial Doppler and diameter of the superficial temporal artery (STA) by high-resolution ultrasonography. All 11 subjects reported headache on the PGE2 day and no subjects reported headache on the placebo day (P = 0.001). During the immediate phase (0–30 min) (P = 0.005) and the postinfusion phase (30–90 min) (P = 0.005), the area under the curve for headache score was significantly larger on the PGE2 day compared with the placebo day. PGE2 caused dilatation of the STA (23.5%; 95% CI 14.0, 37.8) and the MCA (8.3%; 95% CI 4.0, 12.6). We suggest that PGE2 induces headache by activation and sensitization of cranial perivascular sensory afferents.

Changes in cerebral blood flow after acetazolamide: an experimental study comparing near-infrared spectroscopy and SPECT.

Background and purpose:  It is important to find a reliable and bedside method, which can estimate the cerebral blood flow (CBF) of patients in clinical settings. Estimation of CBF by calculating a blood flow index (BFI) using continuous wave near‐infrared spectroscopy (CW‐NIRS) and indocyanine green (ICG) as an iv tracer has been proposed to be a feasible and promising method. To validate if the BFI method can detect relative changes in CBF we compared data with the established method 133Xenon single photon emission computer tomography (133Xe‐SPECT).

Prostaglandin I2 (epoprostenol) triggers migraine-like attacks in migraineurs

Prostacyclin [prostaglandin I2 (PGI2)] activates and sensitizes meningeal sensory afferents. In healthy subjects PGI2 triggers headache in healthy subjects. However, the migraine-eliciting effect of PGI2 has not been systematically studied in patients with migraine. We hypothesized that intravenous infusion of the stable prostacyclin analogue epoprostenol would trigger migraine-like attacks in migraineurs. We infused 10 ng kg−1 min−1 PGI2 or placebo over 25 min in 12 migraineurs without aura in a controlled, double-blind, cross-over study and recorded headache intensity and associated symptons, velocity in the middle cerebral artery (VMCA) and diameter in the superficial temporal artery. In the period 0–14 h, 12 subjects reported headache on PGI2 day compared with three subjects on placebo day (P = 0.004), and six subjects fulfilled the criteria for an experimentally induced migraine-like attack compared with two subjects on placebo (P = 0.219). During infusion and post-infusion phases the AUC under the headache curve on PGI2 was significantly larger than on placebo (P < 0.05). There was a significant VMCA decrease (P = 0.015) and superficial temporal artery diameter increase (P < 0.001) on PGI2 compared with placebo. In conclusion, PGI2 may trigger a migraine-like attack in migraine sufferers. We suggest sensitization of perivascular nociceptors and arterial dilation as the mode of action of PGI2-induced headache and migraine-like attacks.

Prostacyclin (epoprostenol) induces headache in healthy subjects.

Abstract The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I2, (PGI2)) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI2 might induce headache and vasodilatation of cranial vessels. A stable analog of PGI2 epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross‐over, double‐blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (Vmean MCA) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high‐resolution ultrasonography unit. During the immediate phase (0–30 min) and the post‐infusion phase (30–90 min), 11 subjects reported headache on the PGI2 day and no subjects reported headache on the placebo day (p = 0.002). During epoprostenol (0–30 min) and in the post‐infusion phase (30–90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p = 0.005). PGI2 caused headache associated with the dilatation of STA (AUC, p < 0.001), but no significant dilatation of the MCA (AUC, p = 0.508). These data indicate that PGI2 induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.

Carbachol induces headache, but not migraine-like attacks, in patients with migraine without aura.

Carbachol induces headache in healthy subjects, but the migraine eliciting effect of carbachol has not previously been studied. We hypothesized that the cholinomimetic agonist carbachol would induce headache and migraine-like attacks in migraineurs. Carbachol (3 µg/kg) or placebo was randomly infused into 18 patients with migraine without aura in a double-blind crossover study. Headache was scored on a verbal rating scale from 0 to 10. Velocity in the middle cerebral artery (VMCA) and diameter of the superficial temporal artery (STA) were recorded. Fifteen patients experienced headache after carbachol compared with eight after placebo (P = 0.039). There was no difference in incidence of migraine-like attacks after carbachol (n = 8) compared with placebo (n = 6) (P = 0.687). Carbachol caused a decrease in VMCA (P = 0.044), but no change in STA (P = 0.089) compared with placebo. The study demonstrated that carbachol provocation is not a good model for experimental migraine.

Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D2 (PGD2)

Introduction: Prostaglandins (PGs) are involved in nociception and mast cell degranulation. Prostaglandin D2 (PGD2) is a vasodilatator released during mast cell degranulation. The headache-eliciting effect of PGD2 has not been studied in man. Subjects and methods: Twelve healthy volunteers were randomly allocated to receive intravenous infusion of 384 ng/kg/min PGD2 over 25 min in a placebo-controlled, double-blind cross-over study. We recorded headache intensity and associated symptoms, velocity in the middle cerebral artery (VMCA) and diameter of the superficial temporal artery (STA) and radial artery (RA) using ultrasonography. Results: In the period 0–14 h, 11 subjects reported headache on PGD2 compared to one subject on placebo (P = 0.002). During the in-hospital phase (0–120 min), the area under the headache curve was larger on PGD2 compared to placebo (P < 0.05). Median peak headache, 1 (0–1), occurred 10 min after start of PGD2 infusion. There was no difference in incidence of headache in the post-hospital phase between PGD2 (n = 3) and placebo (n = 1). There was a decrease in VMCA (P < 0.001), increase in STA (P < 0.001) and RA (P < 0.006) diameter during PGD2 infusion compared to placebo. Peak decrease in VMCA was 28.3% after 10 min and peak increase in STA was 55.7% after 20 min on the PGD2 day. Conclusions: The present study shows that PGD2 is a very strong vasodilator of MCA, STA and RA, but causes only mild headache.

Prostaglandins in migraine: update

PURPOSE OF REVIEW This review presents recent findings on the role of prostaglandins in migraine pathophysiology. RECENT FINDINGS Experimental studies have shown that prostaglandins are distributed in the trigeminal-vascular system and its receptors are localized in the trigeminal ganglion and the trigeminal nucleus caudalis. Prostaglandins were found in smooth muscles of cranial arteries, and functional studies in vivo showed that prostaglandins induced dilatation of cranial vessels. Human studies showed that intravenous infusion of vasodilating prostaglandins such as prostaglandin E₂ (PGE₂), prostaglandin I₂ (PGI₂) and prostaglandin D₂ (PGD₂) induced headache and dilatation of intra-cranial and extra-cranial arteries in healthy volunteers. In contrast, infusion of non-dilating prostaglandin F₂α (PGF₂α) caused no headache or any vascular responses in cranial arteries. PGE₂ and PGI₂ triggered migraine-like attacks in migraine patients without aura, accompanied by dilatation of the intra-cerebral and extra-cerebral arteries. A novel EP4 receptor antagonist could not prevent PGE₂-induced headache in healthy volunteers. SUMMARY Recent in-vitro/in-vivo data demonstrated presence and action of prostaglandins within the trigeminal pain pathways. Migraine induction after intravenous administration of PGE₂ and PGI₂ suggests a specific blockade of their receptors, EP and IP respectively, as a new potential drug target for the acute treatment of migraine.

Sources of variability of resting cerebral blood flow in healthy subjects: a study using 133Xe SPECT measurements

Measurements of cerebral blood flow (CBF) show large variability among healthy subjects. The aim of the present study was to investigate the relative effect of established factors influencing CBF on the variability of resting CBF. We retrospectively analyzed spontaneous variability in 430 CBF measurements acquired in 152 healthy, young subjects using 133Xe single-photon emission computed tomography. Cerebral blood flow was correlated positively with both end-tidal expiratory PCO2 (PETCO2) and female gender and inversely with hematocrit (Hct). Between- and within-subject CO2 reactivity was not significantly different. Including PETCO2, Hct and gender in the model reduced between-subject and within-subject variance by 14% and 13.5%, respectively. Withinsubject variability was mainly influenced by PETCO2 and between-subject variability mostly by Hct, whereas gender appeared to be of little added value when Hct was also accounted for. The present study confirms large between-subject variability in CBF measurements and that gender, Hct, and PETCO2 explain only a small part of this variability. This implies that a large fraction of CBF variability may be due to unknown factors such as differences in neuron density or metabolism that could be subject for further studies.

The cholinomimetic agent carbachol induces headache in healthy subjects.

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 μg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0–10. Velocity in the middle cerebral artery (Vmca) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0–30 min) (P = 0.042) and in the postinfusion period (30–90 min) (P = 0.027). Carbachol infusion caused a drop in Vmca (P = 0.003) and an increase in STA diameter (P = 0.006), but no increase in the RA diameter (P = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.