Sage Journals: Discover world-class research

Abstract

The purpose of this study was to assess the sensitivity of 5-HT_1D receptors in patients with episodic cluster headache using sumatriptan as a pharmacological probe. The drug, a selective 5-HT_1B/1D agonist, stimulates the secretion of growth hormone and inhibits the release of prolactin, adrenocorticotropic hormone (ACTH) and cortisol. These effects may be used to explore the function of serotonergic systems in vivo. We administered subcutaneous sumatriptan and placebo to 20 patients with cluster headache (10 in the active phase and 10 in the remission period) and to 12 controls. The sumatriptan-induced increase of growth hormone concentrations was significantly (P < 0.05) blunted in patients with active cluster headache. Prolactin and ACTH responses to the drug were significantly (P < 0.05) reduced in patients with cluster headache, both in the active and in the remission period. Our results suggest that cerebral serotonergic functions mediated by 5-HT_1D receptors are altered in patients with episodic cluster headache.

Keywords

Sumatriptan growth hormone prolactin cluster headache

Introduction

The aetiological and pathophysiological mechanisms of cluster headache (CH), one of the most severe primary headache syndromes, are still largely unknown (1). The signature feature of this disorder is its rhythmicity: the disease displays both a circadian periodicity in pain attacks and a circannual periodicity in cluster periods. The cyclic occurrence of the headache attacks suggested a dysfunction of the circadian timing system within the central nervous system (2, 3).

Several endocrine studies have shown alterations in the cyclic secretion of melatonin, cortisol, testosterone, gonadotrophins, prolactin, and thyrotropin, both in the active period and in the remission phase of the disease, suggesting evidence for hypothalamic involvement in CH (4–6). Recent studies with positron emission tomography and with voxel-based morphometry provided additional evidence for hypothalamic activation in the pathogenesis of CH attacks (7, 8).

To investigate further hypothalamic involvement in CH, we decided to use the neuroendocrine challenge paradigm, a strategy that provides a ‘window’ on central neurotransmitter function in vivo (9). A previous challenge study, performed with m-CPP, showed impaired central serotonergic function in patients with episodic CH (10). However, m-CPP is a drug characterized by a large variability in pharmacokinetic and pharmacodynamic parameters and it is doubtful whether it is a useful compound for challenge tests (11). Sumatriptan is a selective 5HT_1B/1D receptor agonist effective in the treatment of CH attacks (12). Several studies in healthy volunteers have shown that the drug induces a significant increase in growth hormone (GH) plasmatic concentrations and a reduction of prolactin (PRL), adrenocorticotropic hormone (ACTH) and cortisol secretion (13–15). Studies in experimental animals have shown these effects are mediated through the activation of hypothalamic 5-HT_1D receptors (16). Sumatriptan does not easily cross the blood–brain barrier but may reach hypothalamic nuclei trough circumventricular organs (17). The neuroendocrine effects induced by sumatriptan administration have been used as a pharmacological tool in several psychiatric and neurological diseases in order to explore cerebral serotonergic functions in vivo(18–22).

The purpose of our study was to assess the sensitivity of 5HT_1D receptors in patients with episodic CH using subcutaneous sumatriptan as a pharmacological probe. We administered the drug and a placebo in CH patients, both in the active phase and in the remission period of the disease, to verify the hypothesis of an abnormal sensitivity of cerebral 5-HT_1D receptors in the disease.

Methods

Subjects

Twenty patients with episodic CH (three females, 17 males; mean age ± SD 40.0 ± 10.9 years) were recruited from the out-patient population at the Headache Centre of the University of Torino, Italy. The diagnosis of episodic CH was made according to the International Headache Society (IHS) criteria (23). Ten patients (one female, nine males; mean age ± SD 43.3 ± 9.1 years) were in the active cluster period while 10 patients (two females and eight males; mean age ± SD 36.7 ± 11.7 years) were in the remission period (at least 2 months after the last headache attack). Patients with mood or anxiety disorders were excluded after administration by a trained psychologist of the State-Trait Anxiety Inventory-X1, -X2 (STAI-X1 and STAI-X2) (24), and the Beck's Depression Inventory (BDI) (25) (cut-off limits STAI-X1 = 45 for women and 42 for men; STAI-X2 = 49 for women and 45 for men; BDI = 12 for men and 15 for women). Patients did not take any prophylactic drug for at least 4 weeks prior to testing. CH patients in the active phase were not allowed to use analgesic drugs for a 24-h period prior to drug administration. Six out of 10 patients in the active group and four out of 10 patients in the remission group had never used subcutaneous sumatriptan for treatment of CH.

Twelve healthy volunteers (three females, nine males; mean age ± SD 37.1 ± 9.7 years), matched for age, sex and phase of the menstrual cycle, served as controls. All subjects gave their informed consent to the study. Demographic and clinical characteristics of patients with CH and healthy controls are shown in Table 1.

Table 1

Demographic and clinical characteristics of patients with cluster headache and controls

	Cluster headache patients, active phase	Cluster headache patients, in remission	Healthy controls
Age (years)	43.3 ± 9.1	36.7 ± 11.7	37.1 ± 9.7
Males	9	8	9
Females	1	2	3
Age at onset of the disease ± SD (years)	30.3 ± 9.3	24.4 ± 6.2	–
Duration of the disease ± SD (years)	13.0 ± 7.1	12.1 ± 10.3	–
Mean duration of the cluster period (days)	44.5 ± 15.3	42.1 ± 14.5	–
Time since last attack (days)	–	234 ± 102.6	–
Positive family history for cluster headache	1	0.	–

Procedures

The study was conducted at the Headache Centre of the University of Torino, Italy, according to a standardized protocol. Each subject underwent two tests, one with subcutaneous sumatriptan (6 mg) and the other with placebo (2 ml subcutaneous saline), in a double-blind fashion. In each subject the tests were separated by 3–6 days. Testing began at 09.00 h after overnight fasting. All subjects were confined to bed and were not allowed to eat or sleep. An indwelling intravenous catheter was inserted in a forearm vein and kept patent with a slow infusion of 0.9% NaCl. A 45-min period was allowed for relaxation. Two baseline blood samples (−15 and 0 min) were taken. Subsequent blood samples were taken at +15, +30, +45, +60 and +90 min after injection.

Assays

Blood samples were collected into sterile tubes. Tubes were immediately centrifuged at 4°C and the plasma was stored at −80°C until assayed. Plasma GH, PRL, ACTH and cortisol concentrations were measured using commercially available radioimmunoassay and immunoradiometric assay kits (HGH-CTK and PRL-CTK, Sorin, Saluggia, Italy; ACTH Allegro, Nichols Institute, San Juan Capistrano, CA, USA; CORT-CTK-125, Sorin). The sensitivity of GH, PRL, ACTH and cortisol assays were 0.15 µg/l, 0.49 µg/l, 1 pg/ml, and 0.5 ng/ml, respectively. The intra-assay and interassay coefficients of variation were 5.1% and 5.4% for GH, 2.5% and 7.7% for PRL, 3% and 7.8% for ACTH, and 3.8% and 5.7% for cortisol, respectively. All samples from each subject were analysed in the same assay.

Statistical analysis

Statistical evaluation was performed using SigmaStat, version 1.0 (Jandel Corp., San Rafael, CA, USA 1994). The hormonal responses to drug administration were evaluated calculating both the means of delta (Δ) values (point value − T₀ value) and Δ peaks (maximum change from T₀ value). For statistical analyses, anova followed by a Dunnet's test for multiple comparison, Student's t-test for unpaired data and Spearman's correlation test were used. Data are reported as mean ± SEM. The level of statistical significance was taken at P < 0.05.

Results

Adverse events after sumatriptan injection were reported by both healthy controls (58.3%) and CH patients (65%). All the adverse events were described as mild in severity and were transient. The most frequently reported were heaviness and pressure on the chest (62.5%), warmth (37.5%) and dizziness (9.4%).

Table 2 shows both the absolute hormonal concentrations (±SEM) and the Δ AUC (area under the curve after subtraction of basal values) in patients and in healthy controls. Basal GH, PRL, ACTH and cortisol concentrations were not significantly different in controls and in patients with CH, either in the active phase or in the remission period.

Table 2

Growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH) and cortisol (CORT) concentrations in patients with cluster headache and controls

		0 min	15 min	30 min	45 min	60 min	90 min	Δ AUC
CH patients in the active phase	GH	0.63 ± 0.47	1.08 ± 0.63	2.56 ± 1.67	2.86 ± 1.90	1.96 ± 1.39	0.63 ± 0.42	107.17 ± 73.69
	PRL	4.00 ± 0.52	4.03 ± 0.58	3.53 ± 0.51	3.56 ± 0.63	3.41 ± 0.56	3.42 ± 0.57	−46.87 ± 12.14
	ACTH	23.49 ± 2.71	23.21 ± 1.96	20.70 ± 1.66	19.10 ± 1.41	20.88 ± 1.79	22.23 ± 2.04	−299.77 ± 176.41
	CORT	93.11 ± 9.85	84.23 ± 7.84	81.37 ± 6.72	72.73 ± 6.45	67.73 ± 5.86	64.15 ± 7.31	−2136.60 ± 411.23
CH patients in the remission phase	GH	1.44 ± 1.22	2.00 ± 0.96	6.39 ± 2.19	7.42 ± 1.99	5.62 ± 1.20	2.25 ± 0.51	297.90 ± 132.26
	PRL	3.59 ± 0.49	3.46 ± 0.47	3.04 ± 0.42	2.78 ± 0.32	2.63 ± 0.36	2.51 ± 0.30	−75.45 ± 17.80
	ACTH	1 8.48 ± 4.29	22.94 ± 5.72	18.41 ± 4.30	15.74 ± 3.37	12.85 ± 2.89	14.11 ± 2.96	−391.12 ± 230.10
	CORT	105.27 ± 12.66	109.94 ± 14.05	105.08 ± 12.39	95.06 ± 11.69	81.22 ± 10.12	72.20 ± 7.59	−1680.22 ± 592.40
Healthy controls	GH	2.20 ± 0.90	3.94 ± 1.02	7.25 ± 2.42	9.01 ± 4.04	7.95 ± 4.32	3.96 ± 2.59	375.61 ± 260.94
	PRL	6.84 ± 1.66	6.63 ± 1.66	5.66 ± 1.40	5.73 ± 1.58	5.74 ± 1.15	5.07 ± 1.35	−161.04 ± 52.59
	ACTH	24.56 ± 5.37	30.64 ± 8.15	25.48 ± 5.76	19.72 ± 4.71	17.48 ± 3.51	12.34 ± 1.12	−473.52 ± 601.45
	CORT	119.38 ± 15.98	137.46 ± 17.39	126.88 ± 17.76	111.86 ± 15.96	103.24 ± 14.84	84.08 ± 11.48	−716.80 ± 1113.90

Values are mean ± SEM. Δ AUC, Area under the curve after subtraction of basal values; GH, µg/l; PRL, µg/l; ACTH, pg/ml; CORT, ng/ml.

Figure 1 shows the effects of sumatriptan administration on GH concentrations in controls and in patients with CH. The administration of sumatriptan induced an increase of GH concentrations both in controls and in patients with CH. However, in patients with active CH, the GH increase after sumatriptan administration was significantly blunted in comparison with controls (P < 0.05 at time +15 min and +30 min as Δ values, left of the figure; P < 0.05 as Δ peak, right of the figure) and with patients with CH in the remission period (P < 0.05 at time +45 min, +60 min and +90 min as Δ values, left of the figure; P < 0.05 as Δ peak, right of the figure).

Figure 1

Mean changes in growth hormone (GH) secretion after sumatriptan (6 mg, s.c., at 0 min) in healthy controls and in patients with episodic cluster headache during the active phase and in remission. On the left, values are expressed as Δ values (▪, active; □, remission; ○, control), on the right as Δ peaks. Vertical bars indicate SEM. ∗P < 0.05 in comparison with controls; †P < 0.05 in comparison with cluster headache patients in the remission phase.

Figure 2 shows the effects of sumatriptan administration on PRL secretion. As expected, the drug induced a reduction of hormone plasma concentrations. The inhibition of PRL secretion, in comparison with controls, was significantly less marked both in patients with active CH (P < 0.05 at time +60 min as Δ values, left of the figure; P < 0.05 as Δ peak, right of the figure) and in patients with CH in the remission period (P < 0.05 as Δ peak, right of the figure).

Figure 2

Mean changes in prolactin (PRL) secretion after sumatriptan (6 mg, s.c., at 0 min) in healthy controls and in patients with episodic cluster headache during the active phase and in remission. On the left, values are expressed as Δ (▪, active; □, remission; ○, control), on the right as Δ peaks. Vertical bars indicate SEM. ∗P < 0.05 in comparison with controls.

Figure 3 shows the effects of sumatriptan administration on ACTH secretion. After an initial increase of ACTH concentrations, a progressive reduction of hormone secretion was observed. In patients with active CH the reduction of ACTH secretion was significantly reduced in comparison with both controls (P < 0.05 at time +90 min as Δ values, left of the figure) and with CH patients in the remission period (P < 0.05 at time 60 min and 90 min as Δ values, left of the figure). In patients with CH in the remission phase there was a significant reduction of ACTH secretion in comparison with controls (P < 0.05 at time +90 min as Δ values, left of the figure). The administration of sumatriptan induced a reduction in cortisol plasma concentrations. However, multiple comparison of controls and patients with CH showed no significant difference in the response to the challenge drug.

Figure 3

Mean changes in adrenocorticotropic hormone (ACTH) secretion after sumatriptan (6 mg, s.c., at 0 min) in healthy controls and in patients with episodic cluster headache during the active phase and in the remission period. On the left, values are expressed as Δ values (▪, active; □, remission; ○, control), on the right as Δ peaks. Vertical bars indicate SEM. ∗P < 0.05 in comparison with controls; †P < 0.05 in comparison with cluster headache patients in the remission phase.

No significant relation was found between the clinical characteristics of CH and the hormonal responses, expressed as Δ peaks. No significant difference in hormonal responses was found between CH patients who used sumatriptan for the first time and patients who used the drug in previous cluster periods.

Discussion

The aim of our study was to evaluate the sensitivity of cerebral 5-HT_1D receptors in patients with episodic CH. In the acute phase of the disease, CH patients showed a significant impairment of GH, PRL and ACTH secretion after sumatriptan injection. During the remission phase, we observed the persistence of an abnormal secretion of both PRL and ACTH. Our data suggest the presence of a significant down-regulation of 5-HT_1D receptors in both phases of the disease.

This is the first study to measure 5-HT_1D receptor sensitivity in patients with CH using sumatriptan as a pharmacological probe, and the findings of this study must be considered preliminary. However, our data are in accord with the results of previous challenge studies that suggested an impairment of hypothalamic function in the disease. The thyroid-stimulating hormone (TSH) response to thyroid-releasing hormone (TRH) administration was significantly lower in patients with active CH in comparison with controls (26). Using both the insulin tolerance test and the ovine corticotrophin-releasing hormone test, Leone et al. (27, 28) found an altered responsiveness of hypothalamic pituitary–adrenal (HPA) axis in patients with CH, both in active cluster and in the remission phase of the disease. Our study confirms previous studies showing an impairment of both HPA axis and prolactin secretion in CH (4, 5) and provides new data concerning a derangement of the mechanisms regulating GH secretion. All these neuroendocrine findings are in agreement with recent neuroimaging studies that provided convincing data concerning hypothalamic involvement and activation in CH attacks (7, 8).

The main finding of this study is the demonstration of a selective impairment of cerebral 5-HT_1D receptor-mediated functions in CH. A previous study with m-CPP (10) suggested impaired central serotonergic function in patients with active CH. However, m-CPP interacts both with several subtypes of serotonin receptors (5-HT_2B, 5-HT_2C, 5-HT_1A) and with α₂-adrenergic receptors. In contrast, sumatriptan is a highly selective 5-HT_1B/1D receptor agonist and the neuroendocrine effects induced by this drug are strictly related to the activation of cerebral serotonergic systems.

It is well known that serotonergic neurones play an important but complex role in the regulation of pain within the central nervous system (29). 5-HT is a neurotransmitter both in the pathways descending from the brain stem to the spinal dorsal horn and in the ascending antinociceptive pathways (30, 31). The multiple effects of 5-HT on pain transmission are mediated through the activation of both 5-HT1 and 5-HT2 receptor subtypes (32). The serotonergic dysfunction found in patients with CH may explain reduced pain threshold found in these patients (33) In addition, it is of interest to note that lithium, a drug effective in the prophylaxis of CH, significantly increases the activity of the cerebral serotonergic systems (34, 35).

In conclusion, our study provides evidence of a selective involvement of cerebral serotonergic systems in CH patients, both in the active phase and in the remission period. Further studies are needed to evaluate whether this finding is of relevance to pathophysiology and prophylactic therapy of cluster headache.

Footnotes

Acknowledgements

This research was supported by a 2000 grant from M.U.R.S.T., Italy.

References

Aurora

. Etiology and pathogenesis of cluster headache. Curr Pain Headache Rep 2002; 6: 71–5.

Pringsheim

. Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 2002; 29: 33–40.

Dodick

Rozen

Goadsby

Silberstein

. Cluster headache. Cephalalgia 2000; 20: 787–803.

Waldenlind

Gustafsson

. Prolactin in cluster headache: diurnal secretion, response to thyrotropin-releasing hormone, and relation to sex steroids and gonadotropins. Cephalalgia 1987; 7: 43–54.

Leone

Bussone

. A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia 1993; 13: 307–9.

Leone

Lucini

D'Amico

Moschiano

Maltempo

Fraschini

Twenty-four-hour melatonin and cortisol plasma levels in relation to timing of cluster headache. Cephalalgia 1995; 15: 224–9.

May

Bahra

Buchel

Frackowiak

Goadsby

. Hypothalamic activation in cluster headache attacks. Lancet 1998; 352: 275–8.

May

Ashburner

Buchel

McGonigle

Friston

Frackowiak

Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 1999; 5: 836–8.

Gordon

Lipton

Brown

van Praag

. The neuroendocrine challenge paradigm in headache research. Cephalalgia 1995; 15: 292–6.

10.

Leone

Attanasio

Croci

Libro

Grazzi

D'Amico

The m-chlorophenylpiperazine test in cluster headache: a study on central serotoninergic activity. Cephalalgia 1997; 17: 666–72.

11.

Gijsman

Van Gerven

Tieleman

Schoemaker

Pieters

Ferrari

Pharmacokinetic and pharmacodynamic profile of oral and intravenous meta-chlorophenylpiperazine in healthy volunteers. J Clin Phychopharmacol 1998; 18: 289–95.

12.

Gobel

Lindner

Heinze

Ribbat

Deuschl

. Acute therapy for cluster headache with sumatriptan: findings of a one-year long-term study. Neurology 1998; 51: 908–11.

13.

Franceschini

Cataldi

Garibaldi

Cianciosi

Scordamaglia

Barreca

The effects of sumatriptan on pituitary secretion in man. Neuropharmacology 1994; 33: 235–9.

14.

Boeles

Williams

Campling

Goodall

Cowen

. Sumatriptan decreases food intake and increases plasma growth hormone in healthy women. Psychopharmacology 1997; 129: 179–82.

15.

Entwisle

Fowler

Thomas

Eckland

Lettis

York

The effects of oral sumatriptan, a 5-HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man. Br J Clin Pharmacol 1995; 39: 389–95.

16.

Valverde

Penalva

Dieguez

. Influence of different serotonin receptor subtypes on growth hormone secretion. Neuroendocrinology 2000; 71: 145–53.

17.

Ganong

. Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 2000; 27: 422–7.

18.

Yatham

Zis

Lam

Tam

Shiah

. Sumatriptan-induced growth hormone release in patients with major depression, mania and normal controls. Neuropsychopharmacology 1997; 17: 258–63.

19.

Cleare

Murray

Sherwood

O'Keane

. Abnormal 5-HT_1D receptor function in major depression: a neuropharmacological challenge study using sumatriptan. Psychol Med 1998; 28: 295–300.

20.

Volpi

Caffarra

Scaglioni

Boni

Saginario

Chidera

Defective 5-HT1-receptor-mediated neurotransmission in the control of growth hormone secretion in Parkinson's disease. Neuropsychobiology 1997; 35: 79–83.

21.

Pinessi

Rainero

Savi

Valfrè

Limone

Calvelli

Effects of subcutaneous sumatriptan on plasma growth hormone concentrations in migraine patients. Cephalalgia 2000; 20: 223–7.

22.

Rainero

Valfre

Savi

Gentile

Pinessi

Gianotti

Neuroendocrine effects of subcutaneous sumatriptan in patients with migraine. J Endocrinol Invest 2001; 24: 310–4.

23.

Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Cephalalgia 1988; 8 (Suppl. 7):1–96.

24.

Spielbeger

Gorsuch

Luschene

. State-trait anxiety inventory. Palo Alto: Consulting Psychologists Press, 1970.

25.

Beck

Steer

. BDI: Beck depression inventory manual. San Antonio: The Psychological Corporation, 1987.

26.

Bussone

Frediani

Leone

Grazzi

Lamperti

Boiardi

. TRH test in cluster headache. Headache 1988; 28: 462–4.

27.

Leone

Zappacosta

Valentini

Colangelo

Bussone

. The insulin tolerance test and the ovine corticotrophin-releasing hormone test in episodic cluster headache. Cephalalgia 1991; 11: 269–74.

28.

Leone

Maltempo

Gritti

Bussone

. The insulin tolerance test and ovine corticotrophin-releasing-hormone test in episodic cluster headache. II. Comparison with low back pain patients. Cephalalgia 1994; 14: 357–64.

29.

Messing

Lytle

. Serotonin-containing neurons: their possible role in pain and analgesia. Pain 1977; 4: 1–21.

30.

Wang

Nakai

. The dorsal raphe: an important nucleus in pain modulation. Brain Res Bull 1994; 34: 575–85.

31.

Gear

Levine

. Antinociception produced by an ascending spino-supraspinal pathway. J Neurosci 1995; 15: 3154–61.

32.

Eide

Hole

. The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity. Cephalalgia 1993; 13: 75–85.

33.

Bono

Antonaci

Sandrini

Pucci

Rossi

Nappi

. Pain pressure threshold in cluster headache patients. Cephalalgia 1996; 16: 62–6.

34.

Price

Charney

Delgado

Heninger

. Lithium and serotonin function: implications for the serotonin hypothesis of depression. Psychopharmacology 1990; 100: 3–12.

35.

Sharp

Bramwell

Lambert

Grahame-Smith

. Effect of short- and long-term administration of lithium on the release of endogenous 5-HT in the hippocampus of the rat in vivo and in vitro. Neuropharmacology 1991; 30: 977–84.

Abnormal 5-HT 1D Receptor Function in Cluster Headache: A Neuroendocrine Study with Sumatriptan

Abstract

Keywords

Introduction

Methods

Subjects

Procedures

Assays

Statistical analysis

Results

Discussion

Footnotes

Acknowledgements

References