Prostaglandin E 2 (PGE 2 ) Induces Headache in Healthy Subjects

Abstract

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 (V_MCA) 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.

Keywords

headache vascular cerebral blood flow middle cerebral artery

Introduction

Neurovascular headaches may originate from activation and sensitization of cranial perivascular afferents (1). The throbbing nature of migraine pain, head pain and corresponding arterial dilation after glyceryl trinitrate (2, 3), effect of arterial compression and dilation of arteries reported during attacks (4, 5) and animal models of migraine (1) suggest that vascular input may play an important role in generation of headache. However, it is still a matter of intense debate to what extent the vascular input contributes to head pain. Animal models suggest that mechanical dilation is not sufficient to sensitize perivascular afferents (6) and that release of inflammatory mediators by mast cell degranulation may play a key role in generation of head pain (7). The present human model has proven effective in the development of new principles for the treatment of migraine (2, 8–10).

Prostanoids such as prostaglandin E₂ (PGE₂) have been implicated in various experimental and clinical pain conditions (11). PGE₂ is produced upon stimulation in cerebral endothelial cells (12) and mast cells (13). PGE₂ released from endothelial cells causes strong dilation of cerebral vessels (14, 15). Furthermore, chemical and electrical stimulation of the trigeminal ganglion releases PGE₂ from the dura mater (16), and PGE₂ has been shown to sensitize sensory afferents (17). These data suggest that PGE₂ may be involved in the pathophysiology of neurovascular headache.

Early open studies reported that PGE₂ might cause a migraine-like pain in humans (18). However, the headache-eliciting effects of PGE₂ have not been studied in a double-blind fashion, and data in animal models cannot be directly extrapolated to humans. We hypothesized that PGE₂ may induce headache in healthy subjects accompanied by dilatation of intra- and extracranial arteries. Therefore, we aimed to study the headache-eliciting effect of PGE₂ and to correlate any headache to the effect of PGE₂ on cerebral and extracerebral arteries and cerebral blood flow (CBF) in healthy subjects in a double-blind, crossover study.

Design and methods

Pilot experiment

Before the main experiment, we conducted an open pilot study to find the optimal dose of PGE₂ that caused a mild to moderate headache on a verbal rating scale (VRS) from 0 to 10 (0, no headache and 10, worst imaginable headache), without intolerable adverse effects and with detectable changes in mean blood flow velocity of the middle cerebral artery (V_MCA) by transcranial Doppler (TCD). Three subjects (two male and one female) received intravenous PGE₂ in stepwise increasing doses of 0.20, 0.40 and 0.60 μg kg⁻¹ min⁻¹. Each infusion lasted 25 min followed by a 60-min wash-out. The results of the pilot study showed that 0.40 μg kg⁻¹ min⁻¹ of PGE₂ induced a mild to moderate headache in three subjects (VRS, range 1–3), was well tolerated and caused a 13.4% decrease in V_MCA.

Main experiment

We recruited 14 healthy subjects (eight male and six female), mean age 22.1 years (range 19–26 years). Exclusion criteria were: a history of migraine or any other type of headache (except episodic tension-type headache less than once a month); any daily medication apart from oral contraceptives; serious somatic or psychiatric diseases. Subject 9 had a family history of migraine. The study was approved by the Ethics Committee of the County of Copenhagen (H-KA-20060026), Danish Medicines Agency, and the Danish Data Protection Agency and was undertaken in accordance with the Helsinki Declaration of 1964, as revised in Edinburgh in 2000. The study was registered on http://www.clinicaltrials.gov and monitored by the Good Clinical Practice unit at Copenhagen University Hospital. All subjects gave informed consent to participate.

Experimental design

In a double-blind, placebo-controlled, crossover design, the subjects were randomly allocated to receive PGE₂ 0.40 μg kg⁻¹ min⁻¹ or placebo (isotonic saline) over 25 min on 2 days, separated by at least a week. The central pharmacy performed the randomization and prepared the study drug. The randomization code remained in the hospital during the study and was not available to the investigators until the study was complete.

All subjects reported to the laboratory at 08.30 h headache free. Coffee, tea, cocoa or other methylxanthine-containing foods or beverages were not allowed for at least 8 h before start of the study. All procedures were performed in a quiet room, and room temperature was between 20.8 and 24.8°C. Subjects were placed in the supine position and a venous catheter (Venflon^®) was inserted into the right antecubital vein for infusion. The subjects then rested for 30 min before baseline (0) recordings. After baseline measurements, infusion started using a time and volume controlled infusion pump (Braun Perfusor, Melsungen, Germany). Headache intensity, accompanying symptoms, V_MCA, diameter of the superficial temporal artery (STA) and radial artery (RA), end-tidal partial pressure of pCO₂ (P_etCO₂), adverse events and vital signs were recorded at baseline and then every 10 min until 90 min after start of infusion.

CBF measurements by single photon emission computed tomography (SPECT) were performed at baseline, 20 min and 60 min after start of infusion. Subjects were carefully instructed to complete a headache diary with accompanying symptoms according to the International Headache Society (19), including questions concerning premonitory symptoms (tired, yawning, stiff neck, blurred vision, thirst, intolerant/irritable, emotional, difficulty with concentration, any other symptoms) (20) and allodynia (combing, shaving, shower, cold, earrings, eyeglasses, heat, contact lenses, tight clothes, pillow, ponytail, necklace) (21) and any rescue medication every hour until 12 h after discharge from the hospital. Subjects were allowed to take rescue medication of their own choice at any time.

Headache intensity

Headache intensity was recorded on a VRS from 0 to 10 [0, no headache; 1, a very mild headache (including a feeling of pressing or throbbing—pre-pain); 5, moderate headache; 10, worst imaginable headache] (22).

Middle cerebral artery blood flow velocity

V_MCA was recorded bilaterally by TCD with hand-held 2-MHz probes (Multidop X; DWL, Sipplingen, Germany), as previously described (23, 24). All recordings were done by the same skilled examiner (T.W.). P_etCO₂ (end-tidal CO₂) was recorded simultaneously to the TCD measurements using an open mask that caused no respiratory resistance (ProPac Encore^®; Welch Allyn Protocol, Beaverton, OR, USA). V_MCA measurements were performed immediately after CBF measurements. Since regional cerebral blood flow (rCBF_MCA) equals the product of V_MCA and cross-sectional area of the MCA, assuming no change in cerebral blood volume, the relative percentage changes in MCA diameter (Δd) between treatments a and b were calculated as

Δ d = (\sqrt{(V_{MCA (a)} / V_{MCA (b)})} - 1) \times 100 (25) .

Diameter of the superficial temporal artery and radial artery

Diameter of the frontal branch of the left STA and the left RA was measured by a high-resolution ultrasonography unit (20 MHz, bandwidth 15 MHz; Dermascan C; Cortex Technology, Hadsund, Denmark) as previously described (24, 26).

Cerebral blood flow

The examination was performed with the patient in the supine position, in quiet surroundings with eyes closed but ears unplugged. Four markers were drawn on the skin to ensure accurate positioning in each acquisition. P_etCO₂ was measured during each examination (Datex Normocap 200, Roedovre, Denmark). CBF was measured with ¹³³Xe inhalation (Hevesy Laboratory, Ris⊘ National Laboratory, Denmark) and SPECT, using a brain-dedicated gamma camera (Ceraspect; DSI, Waltham, MA, USA). The system uses a stationary annular NaI crystal and a fast rotating collimator. Flow was calculated in each pixel based on the clearance curve, output was the k_i value (27). To obtain CBF values, a partition coefficient (λ) of 0.85 was used. Calculation of flow in the perfusion territories of the major cerebral arteries was performed by fitting standard vascular regions of interest on axial slices of the brain as previously described (28). CBF values were corrected for significant changes in P_etCO₂ by 2% for each mmHg change in P_etCO₂(29). Six subjects were randomly allocated to CBF measurements.

Vital signs

Heart rate (HR) and blood pressure were measured every 10 min by an auto-inflatable cuff (ProPac Encore^®; Welch Allyn Protocol). ECG (Cardiofax V; Nihon-Cohden, Japan) was monitored on an LCD screen and recorded on paper every 10 min.

Data analysis and statistics

Headache scores are presented as median and quartiles. Vascular baseline variables are presented as mean ±s.d. and vascular peak responses after PGE₂ as mean percentage from baseline [95% confidence interval (CI)]. We defined an immediate phase as a period from 0 to 30 min because of a short half-life (< 1 min) of PGE₂ in plasma (30) and a postinfusion phase as a period from 30 to 90 min. We calculated the area under the curve (AUC) according to the trapezium rule (31) to obtain a summary measure and to analyse the differences in response [headache score, V_MCA, diameter of STA and RA, mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, global CBF (gCBF), rCBF and P_etCO₂] between PGE₂ and placebo. Baseline was subtracted before calculating AUC to reduce variation between sessions within subject. Baseline was predefined as an average of −10 min and 0 min before the start of infusion. If there was no difference in V_MCA between hemispheres, the average of the left and the right sides for V_MCA and rCBF_MCA was used in the statistical analysis.

The primary end-points were differences in the AUC for headache score (AUC_{headache 0–30 min}), AUC_{headache 30–90 min}, V_MCA (AUC_VMCA), STA (AUC_STA), RA (AUC_RA) and P_etCO₂ (AUC_PetCO2) between groups in the period 0–30 min. The secondary end-points were differences in HR (AUC_HR), MAP (AUC_MAP), SBP (AUC_SBP) and DBP (AUC_DBP) between groups in the period 0–30 min and 30–90 min. Additional explorative end-points were differences in AUC for all variables in the period 30–90 min. To test the differences between variables (including baseline variables) we used the Wilcoxon signed rank test for headache score and a paired, two-way t-test for vascular data.

gCBF, rCBF_MCA and P_etCO₂ measured during CBF acquisition were also analysed for changes over time for each dose separately with univariate analysis of variance (anova) with the fixed factors subject and time. To reduce mass significance, the following time points were selected for analysis (T0, T20 and T60). If overall differences were found, Dunnett's test was applied to characterize which time points were different from baseline.

We tested for period and carry-over effects for all baseline variables with Mann–Whitney test (headache scores) and independent t-test (vascular variables). All analyses were performed with spss for Windows 14.0 (SPSS Inc., Chicago, IL, USA). Five per cent (P < 0.05) was accepted as the level of significance.

Results

Eleven subjects (six male and five female, mean age 22.5 years, range 19–26 years) completed the study on both study days. One subject (1) was included, but later excluded before the first study day on suspicion of lack of compliance. Two subjects (6 and 13) were drop-outs on the second day (PGE₂ day) due to adverse events. Subject 6 was withdrawn because of drop in MAP of 22% from baseline (security limits were ± 20% from baseline), dizziness, bilateral moderate throbbing headache (VRS 5) associated with phonophobia and aggravation by physical activity. Subject 13 wished to stop the experiment due to an urge to void, powerful low abdominal pain mimicking menstrual pain, and a unilateral mild throbbing headache (VRS 1) associated with nausea. These three subjects were excluded from statistical analysis. There were no differences in baseline recordings for any variables between the two experimental days (Table 1). There was no carry-over or period effect for baseline values of headache, V_MCA, gCBF, rCBF_MCA, STA, RA, MAP or HR (P > 0.05). We found no difference in baseline V_MCA or rCBF_MCA recordings between the left and right side on either active or placebo days (P > 0.05).

Table 1

Mean baseline values (±s.d.) of velocity of blood flow in the middle cerebral artery (V_MCA), global (gCBF) and regional CBF (rCBF_MCA) P_etCO₂, diameter of superficial temporal artery (STA) and radial artery (RA), mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), in 11 healthy subjects on prostaglandin (PG) E₂ and placebo days

Variables	PGE₂	Placebo	P-value
V_MCA	73.12 ± 18.05	72.27 ± 17.50	0.361
gCBF (ml/100 g per min)	53.34 ± 7.57	53.48 ± 6.26	0.943
rCBF_MCA (ml/100 g per min)	53.43 ± 7.65	53.42 ± 6.13	0.995
PetCO₂ (mmHg)	35.83 ± 2.68	35.79 ± 3.33	0.958
STA (mm)	1.05 ± 0.26	1.07 ± 0.25	0.843
RA (mm)	2.18 ± 0.20	2.15 ± 0.18	0.601
MAP (mmHg)	70.86 ± 6.62	71.93 ± 5.18	0.589
SBP (mmHg)	105.04 ± 7.76	107.63 ± 6.76	0.341
DBP (mmHg)	53.77 ± 6.77	54.09 ± 4.89	0.864
HR	56.19 ± 9.15	54.79 ± 1.85	0.315

P-value, paired t-test.

Headache

During the observation period at hospital (0–90 min), 11 subjects reported headache on the PGE₂ day and no subjects reported headache on the placebo day (P = 0.001, McNemar test) (Table 2). During the immediate phase, the AUC_{headache 0–30 min} on the PGE₂ day, 25 (5–70), was significantly larger than on the placebo day, 0 (0–0), (P = 0.005) (Fig. 1). During the postinfusion phase, the AUC_{headache 30–90 min} on the PGE₂ day, 35 (20–90), was significantly larger than on the placebo day, 0 (0–0), (P = 0.005) (Fig. 1). The median peak headache, 2 (0–2), occurred 40 min after start of PGE₂ infusion.

Table 2

Clinical characteristics of PGE₂-induced headache in 11 healthy subjects

Subject	Time (h)	Headache localization/intensity/quality/aggravation	Nausea/photo/phonophobia
2
a		Bilat./1/pressing/yes	–
b	10	Bilat./3/pressing/no	–
3
a		Bilat./1/pressing/no	No/yes/no
b		–	–
4
a		Bilat./2/pressing/yes	Yes/no/no
b		–	–
5
a		Bilat./2/pressing/no	Yes/no/no
b	4	Bilat./2/pressing/yes	–
7
a		Bilat./5/pressing/no	–
b	3	Bilat./1/pressing/yes	–
8
a		Bilat./3/pressing/no	–
b		–	–
9
a		Bilat./2/pressing/no	Yes/no/no
b		–	–
10
a		Bilat./2/pressing/no	Yes/no/no
b	3	Bilat./1/constant/no	–
11
a		Bilat./1/pressing/yes	–
b	3	NS/1/NS/no	–
12
a		Bilat./1/throbbing/no	–
b		–	–
14
a		Bilat./5/throbbing+pressing/yes	Yes/yes/no
b		–	–

a, Peak headache on PGE₂ day and associated symptoms during peak headache, in-hospital phase (0–90 min).

b, Peak headache on PGE₂ day and associated symptoms during peak headache, out-of-hospital phase (1.5–14 h).

NS, not stated.

Figure 1

Median (□), individual active (▪) and placebo (x) headache scores on a verbal rating scale (VRS). There was a significantly higher headache response in the immediate (AUC_{headache 0–30 min}, P = 0.005) and postinfusion (AUC_{headache 30–90 min}, P = 0.005) phases on prostaglandin E₂ day compared with placebo day.

During the delayed phase (1.5–14 h), five subjects reported headache on the PGE₂ day, and three subjects reported delayed headache on the placebo day (P = 0.625, McNemar test) (Table 2). There was no difference in AUC_{headache 30–90 min} between the PGE₂ day, 0 (0–2.50), and the placebo day, 0 (0–0.50) (P = 0.596).

Comparing all individual peak headaches, the peak immediate headache 2 (1–3.5) during the immediate and postinfusion phases on PGE₂ day in subjects reporting delayed headache was identical to subjects not reporting delayed headache.

Comparing all individual peak headaches, the peak median headache was 1 (1–3) in 10 subjects during the infusion phase on PGE₂ day, and this headache was reported to be bilateral (100%), throbbing (30%), constant (100%) and aggravating (20%). During the postinfusion phase peak median headache was 2 (1–2) in 10 subjects, and this headache was reported to be bilateral (100%), throbbing (10%), constant (100%) and aggravating (30%). During the delayed phase peak median headache was 1 (0–2) in five subjects, and this headache was reported to be bilateral (80%), constant (80%) and aggravating (40%).

Middle cerebral artery velocity, diameter and regional cerebral blood flow

The AUC_VMCA was significantly larger on PGE₂ than on placebo during the immediate phase (P = 0.006). There was no difference in the AUC_VMCA during the postinfusion phase (P = 0.362) (Fig. 2). There were no differences in the AUC_PetCO2 recordings during TCD scans between PGE₂ and placebo days, during either the immediate (P = 0.182) or postinfusion phases (P = 0.375).

Figure 2

Individual and mean flow velocities (cm/s) in the middle cerebral arteries (V_MCA) on prostaglandin E₂ compared with placebo day. There was a significant difference in AUC_{VMCA 0–30 min} (P = 0.022).

There was no change in the AUC_{0–60 min} for gCBF (P = 0.275) or for rCBF_MCA (P = 0.221) after PGE₂ compared with placebo. P_etCO₂ measured during CBF acquisition remained unchanged over time on the PGE₂ day (P = 0.060), but decreased significantly on the placebo day (P = 0.025). anova analyses showed that the gCBF and rCBF decreased at 20 min and at 60 min on the placebo day (P < 0.05). After correction for P_etCO₂, we found no differences between (the AUC) and within (anova) the two experimental conditions in AUC in gCBF or rCBF_MCA (P > 0.05). A peak decrease of V_MCA, 13.9% (95% CI 20.6, 7.3), compared with baseline occurred 20 min after start of the PGE₂ infusion, and the relative percentage change in diameter (Δd) was calculated to be 8.3% (95% CI 4.0, 12.6) (Table 3).

Table 3

Maximal mean percentage changes from baseline (95% CI) in vascular variables on PGE₂ day (0–90 min)

Variable	Peak time (min)	PGE₂ (%)
Δd MCA	20	8.3 (4.0–12.6)
V_MCA	20	−13.9 (−20.6–−7.3)
STA	10	23.5 (14.0–37.8)
RA	10	4.4 (−0.2–9.1)
RA	30	−10.0 (−12.3–−7.7)
HR	20	63.3 (46.3–80.4)
MAP	10	−4.5 (−7.6–−1.3)
SBP	70	6.1 (3.1–9.0)
DBP	20	−7.7 (−14.7–−0.6)

MCA, middle cerebral artery; STA, superficial temporal artery; RA, radial artery; HR, heart rate; MAP, mean arterial blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Superficial temporal artery

During the immediate phase, the AUC_{STA 0–30 min} on the PGE₂ day was significantly larger than on the placebo day (P < 0.001) (Fig. 3). In the postinfusion period there was no difference in the AUC_{STA 30–90 min} on the PGE₂ day compared with the placebo day (P = 0.845). The peak responses are presented in Table 3.

Figure 3

Individual and mean diameter (mm) of the superficial temporal artery (STA) on prostaglandin E₂ compared with placebo day. There was a significant difference in the AUC_{STA 0–30 min} (P = 0.035).

Radial artery

There was no difference in the AUC_{RA 0–30 min} (P = 0.856) between PGE₂ day and placebo day. There was a significant difference in the AUC_{RA 30–90 min} (P = 0.001) between PGE₂ day and placebo day. The peak responses are shown in Table 3.

Allodynia and premonitory symptoms

There was no difference in premonitory symptoms between the two experimental days (P > 0.05, McNemar test). On the PGE₂ day the following premonitory symptoms were reported: tiredness (91%), yawning (82%), thirst (55%), stiff neck (27%), intolerant (27%), emotional (18%), difficulty with concentration (18%), slept (9%) and heartbeat and dizziness (9%). On the placebo day, premonitory symptoms were reported as tiredness (55%), yawning (73%), stiff neck (27%), thirst (18%), difficulty with concentration (18%) and dizziness (9%).

There was no difference in reported allodynic symptoms between the two experimental days (P > 0.05, McNemar test).

Arterial blood pressure and heart rate

We found no difference in MAP or SBP between PGE₂ and placebo days during either the immediate (AUC_{MAP 0–30 min}, P = 0.343 and AUC_{SBP 0–30 min}, P = 0.803) or the postinfusion phase (AUC_{MAP 30–90 min}, P = 0.576 and AUC_{SBP 30–90 min}, P = 0.066). There was a significant drop in DBP in the immediate phase (P = 0.002), but no difference in the postinfusion phase (P = 0.494) (Table 3).

AUC_HR was significantly larger on PGE₂ compared with placebo during the immediate (P < 0.001) and postinfusion phase (P < 0.001). The peak responses are shown in Table 3.

Adverse events

Adverse events were recorded and reported during immediate and postinfusion phases (Table 4). All subjects reported adverse events on the PGE₂ day and three subjects reported adverse events on the placebo day.

Table 4

Adverse events were recorded and reported during 0–90 min period

Symptoms	PGE₂	Placebo	P-value
Headache	11	0	0.001
Nausea	6	0	0.031
Photophobia	2	0	0.500
Flushing	10	1	0.002
Palpitation	10	0	0.002
Heat sensation	8	3	0.125
Mandibular pain/tooth pain	3	0	0.250
Feeling cold	3	0	0.250
Pale	3	0	0.250
Prickling sensation in arms/hands/legs	3	0	0.250
Light shortness of breath	3	0	0.250
Muscular pain	3	0	0.250
Uneasiness in the body	2	0	0.500
Bearing-down sensation	2	0	0.500
Light abdominal discomfort	1	0	1.000
Yawning	1	0	1.000
Sensitive skin	1	0	1.000
Painful dorsum of the nose	1	0	1.000
Painful lungs during cough	1	0	1.000
Conjunctival injection	1	0	1.000
Low abdominal pain which mimics menstruation	4	0	0.125

P-value: McNemar test

Discussion

To our knowledge, this is the first human double-blind study to explore a headache-eliciting and vasoactive effect of PGE₂. The major outcome of the present study was that PGE₂ induced extra- and intracranial vasodilation and a mild to moderate headache in healthy subjects. The present study cannot show the precise mechanism of PGE₂-induced headache. Additional studies in both humans and animals are needed to show the underlying mechanisms, but we will discuss possible mechanisms of PGE₂-induced headache.

Vascular mechanisms of PGE₂-induced headache

PGE₂ is a strong vasodilator in animal and human in vitro studies. Vasomotor actions of PGE₂ depend on the type of tissue and type of receptor coupling (32). PGE₂ dilates human MCA in vitro via the EP4-receptor (15). The EP2- and EP4-receptors are associated with smooth muscle relaxation. They are coupled to G_s-receptors causing elevation of intracellular cyclic adenosine 3′, 5′ monophosphate (cAMP) (33). In contrast to prostaglandin I₂ (PGI₂), it appears that dilation by PGE₂ may involve potassium channels (34). Thus, K_ATP and K_ca channels are involved in PGE₂-induced pial artery dilation via cAMP and cyclic guanosine monophosphate pathways (35). Both these pathways have been implicated in the pathophysiology of neurovascular headaches (36, 37).

We have previously explored the role of the vasoactive prostanoid PGI₂ in the generation of headache (38). The number of subjects (n = 11) who reported headache after PGI₂ was the same as in the present study. The median peak headache intensity was slightly higher in the present study (2 vs. 1 on VRS). In contrast to PGI₂, we observed a contraction of RA at 30 min after an initial dilation (10 min) (Table 3 and Fig. 4), but no contraction of MCA or STA. It has been reported that PGE₂ given intravenously, intracarotidly and topically on cerebral arteries mediates both contraction and dilation of the arteries (39). Contraction has been shown in animal basilar and middle cerebral arteries with PGE₂ in high doses (40). Different vasoactive responses to the same dose of PGE₂ in cranial compared with peripheral arteries may reflect different functional roles of PGE₂ in order to ensure sufficient blood flow to more vital organs.

Figure 4

Median headache (▪) and mean percentage changes from baseline for the middle cerebral artery blood flow velocity (V_MCA) (○), diameter of the superficial temporal artery (STA) (▴) and diameter of the radial artery (RA) (•) on prostaglandin E₂ day. Peak decrease in V_MCA was 13.9% at 20 min compared with baseline. Peak increase in STA diameter was 23.5% at 10 min compared with baseline. Peak increase in RA was 4.4% at 10 min compared with baseline and peak decrease in RA was 10.0% at 30 min compared with baseline.

The magnitude of MCA (6.6%) and STA (38.8%) dilation during PGI₂ was similar to dilation in the present study. Vasodilation by PGE₂ was followed by a mild to moderate headache that came somewhat later (40 min after start of infusion) (Fig. 4). This suggests that other mechanisms rather than simple vasodilation are involved in the generation of headache. Mechanical dilation of the blood vessels is not sufficient to sensitize perivascular nociceptors (6). Furthermore, PGE₂ increases permeability of the arterial wall (41) and is therefore able to reach perivascular afferents and sensitize them directly. In the following we will discuss a possible neuronal origin of PGE₂-induced headache.

Neuronal mechanisms of PGE₂-induced headache

The role of prostanoids in nociception is well established. The EP1, EP3 and EP4-receptors associated with PGE₂ are expressed in the dorsal root ganglion neurons (42, 43). A chemical mixture containing various mediators including PGE₂ activates and sensitizes dural nociceptors located on the meningeal vessel wall (6, 44), and infusion of cyclooxygenase (COX)-1/COX-2 inhibitors blocks sensitization in meningeal nociceptors (45). Meningeal mast cells may release inflammatory mediators including PGE₂(13). Conversely, PGE₂ can cause mast cell degranulation that may be suppressed by inhibitors of cAMP via protein kinase A (46). PGE₂ releases calcitonin gene-related peptide (CGRP) (47) in primary sensory neurons. This is particularly relevant because administration of CGRP triggers migraine-like headache (9). Furthermore, it has been shown that PGE₂ increases tetrodotoxin-resistant Na⁺ current (TTX-R I_Na) in nociceptors (48–50). The TTX-R I_Na channels are expressed in mechanosensitive meningeal nociceptors (51, 52), and these channels are involved in both the development and maintenance of acute and chronic inflammatory hyperalgesia (53). Furthermore, PGE₂ increases or sensitizes the transient receptor potential vanilloid type 1 (TRPV1) responses in dorsal root ganglion neurons (54). This would activate TRPV1 and thereby cause spontaneous pain (54). Collectively, these data indicate that PGE₂ in the present study may activate and sensitize meningeal nociceptors and thereby cause head pain.

The question is, does the action of PGE₂ in the central nervous system (CNS) contribute to mechanisms of head pain? The EP2 receptor mRNA is expressed in the dorsal horn of the spinal cord (55), and PGE₂ binding sites have been found in the spinal trigeminal nucleus and lamina I and II of the dorsal horn of the spinal cord (56). Peripheral inflammation up-regulates COX-2 mRNA in the spinal cord (57, 58) and increases production of prostanoids including PGE₂. It has been shown that PGE₂ releases CGRP (59) and nitric oxide (60) in the spinal cord. Furthermore, PGE₂ passes the blood–brain–barrier (61) in a dose-dependent fashion (62) and might have a longer half-life in the CNS compared with plasma-like other prostanoids (62). PGE₂ relieves dorsal horn nociceptive neurons from the inhibitory control by glycinergic neurons (63) via activation of EP2-receptors and a subsequent protein kinase A-dependent block of glycine receptors containing the α₃ subunit (64). In animals, allodynia and hyperalgesia have been reported after intrathecal administration of PGE₂ via EP1 and EP2 receptors (63, 65, 66). Thus, it is plausible to suggest that central mechanisms contribute to the headache reported in the present study.

Concluding remarks

The present study has shown that PGE₂ dilates cephalic arteries in man and causes headache in healthy subjects. The prominent adverse events on the PGE₂ day may have compromised blindness of the present study. However, the adverse events were caused by the physiological response to PGE₂ and could not be avoided. The present double-blind approach is the best possible way of coping with methodological error. We suggest that PGE₂-induced headache is caused by activation and sensitization of meningeal nociceptors. It would be relevant to study a possible migraine-inducing effect of PGE₂.

Footnotes

Acknowledgements

The authors thank lab technicians Lene Elkjær, Annette Foldager and study nurse Kirsten Crawfurd for their dedicated and excellent assistance. The study was supported by grants from the Lundbeck Centre of Neurovascular Signalling (LUCENS) and the Danish Headache Society.

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Prostaglandin E 2 (PGE 2 ) Induces Headache in Healthy Subjects

Abstract

Keywords

Introduction

Design and methods

Pilot experiment

Main experiment

Experimental design

Headache intensity

Middle cerebral artery blood flow velocity

Diameter of the superficial temporal artery and radial artery

Cerebral blood flow

Vital signs

Data analysis and statistics

Results

Headache

Middle cerebral artery velocity, diameter and regional cerebral blood flow

Superficial temporal artery

Radial artery

Allodynia and premonitory symptoms

Arterial blood pressure and heart rate

Adverse events

Discussion

Vascular mechanisms of PGE2-induced headache

Neuronal mechanisms of PGE2-induced headache

Concluding remarks

Footnotes

Acknowledgements

References

Vascular mechanisms of PGE₂-induced headache

Neuronal mechanisms of PGE₂-induced headache