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NEUROPHARMACOLOGY
Headache Group, Institute of Neurology, Queen Square, London, United Kingdom
Received January 4, 2005; accepted March 16, 2005.
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Abstract |
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2-adrenoceptor antagonist, yohimbine, rather than specific dopamine receptor antagonists. The D1 receptor agonist caused a vasoconstriction (P < 0.05) and a blood pressure increase (P < 0.05), which was reversed by yohimbine and therefore 2-adrenoceptor-mediated. None of the specific dopamine receptor antagonists were able to attenuate neurogenic dural vasodilation. Dopamine hydrochloride infusion (P < 0.05) and a D1 receptor agonist were able to attenuate the vasodilation (P < 0.05), with maximal dilation returning after cessation of the dopamine agonist infusion. This response may be due to the vasoconstrictor effects of the 2-adrenoceptor and an action at the D1 receptor. In the intravital model of trigeminal activation, it seems that dopamine receptors do not play a major role and may not present an acute treatment option. Our data do not exclude a role for dopamine receptor modulators in short- or long-term prevention.
). Stimulation of dural sites is painful in humans (Ray and Wolff, 1940), and activation of trigeminal neurons in animal studies causes calcitonin gene-related peptide (CGRP) release (Goadsby et al., 1988) and dural blood vessel dilation (Williamson et al., 1997b). Both the CGRP release (Goadsby and Edvinsson, 1993) and dural blood vessel dilation (Williamson et al., 1997b) are inhibited by the triptans (5-HT1B/1D receptor agonists), which are potent antimigraine compounds (Ferrari et al., 2001). Recent clinical trial evidence suggests that blockade of CGRP receptors has a potent acute antimigraine effect (Olesen et al., 2004).
In addition to the headache phase in migraine, there are also the premonitory and resolution phases, which are characterized by nausea, vomiting, hypotension and drowsiness, and tiredness and mood changes, respectively (Headache Classification Committee of The International Headache Society, 2004). Given that these changes may be a result of monoamine, and specifically dopaminergic neurotransmission, dopamine has been implicated in migraine (Peroutka, 1997; Mascia et al., 1998; Fanciullacci et al., 2000). Additionally, migraine patients seem to show a hypersensitivity to dopamine agonists. Apomorphine, a dopamine receptor agonist, produces more yawning in migraineurs than in age-matched controls (Blin et al., 1991), and piribedil caused increase in cerebral blood flow as well as inducing nausea, vomiting, and hypotension that was blocked by the peripheral D2-receptor antagonist domperidone (Bes et al., 1986). Two small studies have shown domperidone can prevent the occurrence of migraine if it is taken during the premonitory phase (Amery and Waelkens, 1983; Waelkens, 1984). This has led to a dopamine theory of migraine.
Studies performed on cat pial arteries in vivo and middle cerebral arteries in vitro showed that dopamine agonists caused slight vasodilation at very low doses, whereas at higher doses dopamine caused vasoconstriction (Edvinsson et al., 1978a,b). Similarly, dopamine and apomorphine intracarotid infusions caused a dose-dependent vasoconstriction in dog (Villalon et al., 2003), although they found that a selective D1 receptor agonist caused slight vasodilation, as did the effects of dopamine after it was antagonized by a 2-adrenergic receptor antagonist.
Given the effects of dopamine on the cerebral, pial, and carotid arteries as well as the renal and mesenteric vasculature, we wanted to examine what effects dopamine might have on the dural vasculature and therefore whether it may be involved in any direct way in the headache phase of migraine. The intravital microscopy model of trigeminovascular activation uses the reaction of meningeal blood vessel caliber after electrical stimulation of a cranial window as a model of trigeminal nerve fiber activation (Williamson et al., 1997b), and it has proven to be an excellent model in predicting antimigraine efficacy (Williamson et al., 1997b). Previously, the triptans have been shown to attenuate neurogenic dural vasodilation (Williamson et al., 1997b). We looked at the effects of dopamine agonists and antagonists on neurogenic dural vasodilation. We also looked at the direct effects of dopamine and specific D1 and D2 receptor agonists on dural blood vessel caliber. The response of dopamine was also challenged with specific dopamine receptor antagonists as well as 2-adrenoceptor antagonists. We monitored carefully any changes in arterial blood pressure related to dopamine and the various antagonists.
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Materials and Methods |
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Intravital Microscopy
The cranial window was covered with mineral oil (37°C), and a branch of the middle meningeal artery was viewed using an intravital microscope (MV2100; Microvision, Runcorn, UK), and the image was displayed on a television monitor. Dural blood vessel diameter was continuously measure using a video dimension analyzer (Living Systems Instrumentation, Burlington, VT) and displayed with blood pressure on a data analysis system (Spike2 version 4; Cambridge Electronic Design, Cambridge, UK).
Experimental Protocols
Defining Electrical Stimulation Parameters. Electrical stimulation was used to evoke neurogenic dural vasodilation with a bipolar stimulating electrode (NE 200X; Clark Electromedical Instruments, Pangbourne, UK) that was placed on the surface of the cranial window approximately 200 µm from the vessel of interest. The surface of the cranial window was stimulated at 5 Hz, 1 ms for 10 s (Grass stimulator S88; Grass Instruments, Quincy, MA) with increasing voltage until maximal dilation was observed. Subsequent electrically induced responses in the same animal were then evoked using the same voltage.
Effect of Dopamine Receptor Agonists and Dopamine Antagonists on Neurogenic Dural Vasodilation. The effect of dopamine hydrochloride and the specific dopamine receptor agonists A68930
[GenBank]
hydrochloride and (-)-quinpirole hydrochloride on neurogenic dural vasodilation were studied. Dopamine (20 or 40 µg kg-1 min-1), A68930
[GenBank]
hydrochloride (50 µg kg-1 min-1), and (-)-quinpirole hydrochloride (50 µg kg-1 min-1) were intravenously infused at least 10 min after a control response to electrical stimulation. The electrical stimulation was then repeated 5 min into the infusion, and the infusion continued for a further 5 min. At least 10 min after the completion of the dopamine infusion, the electrical stimulation was repeated. The response of dopamine hydrochloride on neurogenic dural vasodilation was also challenged with the 2-adrenoceptor antagonist yohimbine (3 mg kg-1), the D1 receptor antagonist R-(+)-SCH-23390 (1.0 mg kg-1), and the D2 receptor antagonist S-(-)-eticlopride hydrochloride (3.0 mg kg-1). Similarly, the response of A68930
[GenBank]
hydrochloride on neurogenic dural vasodilation was also challenged with yohimbine (3 mg kg-1).
In a separate series of experiments, the neurogenic dural vasodilator response was challenged with a D1 dopamine receptor antagonist, R-(+)-SCH-23390. A control response to electrical stimulation was followed at least 10 min later by an intravenous bolus of R-(+)-SCH-23390 (0.3 mg kg-1) and followed 5 min later by a repeat electrical stimulation. This protocol was repeated for an increased dose of R-(+)-SCH-23390 (1.0 mg kg-1) in the same animal. A similar series of experiments were also completed with a D2 dopamine receptor antagonist, S-(-)-eticlopride hydrochloride (0.3, 1.0, and 3.0 mg kg-1); a D3 dopamine receptor antagonist, U99194A maleate (0.3, 1.0, and 3.0 mg kg-1); and a D4 dopamine receptor antagonist, L-745,870 hydrochloride (0.3, 1.0, and 3 mg kg-1).
Effects of Dopamine Receptor Agonists and Antagonists on Dural Blood Vessel Caliber. The effect of dopamine hydrochloride, the D1 receptor agonist A68930 [GenBank] hydrochloride, and the D2 receptor agonist (-)-quinpirole hydrochloride on dural blood vessel diameter was studied. Increasing doses of dopamine hydrochloride (0.5, 1, 2, 5, 10, 15, 20, and 40 µg kg-1 min-1), A68930 [GenBank] hydrochloride (1, 10, and 50 µg kg-1 min-1), and (-)-quinpirole (1, 10, and 50 µg kg-1 min-1) were administered as an infusion for 10 min each, with a gap of 5 min between each increase of dose. In a separate series of experiments, the effects of dopamine hydrochloride were challenged with a D1 dopamine receptor antagonist, R-(+)-SCH-23390. Dopamine was infused at 40 µg kg-1 min-1 for 10 min, and thereafter a further 10 min R-(+)-SCH-23390 (0.3 mg kg-1) was administered, and 5 min later a 10-min dopamine infusion was repeated. A further 10 min after the dopamine infusion was completed, an increased dosage of R-(+)-SCH-23390 (1.0 mg kg-1) was administered, and the dopamine infusion was repeated. A similar series of experiments was also completed with a D2 dopamine receptor antagonist, S-(-)-eticlopride hydrochloride (0.3, 1.0, and 3.0 mg kg-1); a D3 dopamine receptor antagonist, U99194A maleate (0.3, 1.0, and 3.0 mg kg-1); and a D4 dopamine receptor antagonist, L-745,870 hydrochloride (0.3, 1.0, and 3 mg kg-1).
In a separate series of experiments, we examined the response of 40 µg kg-1 min-1 dopamine hydrochloride infusion with yohimbine, the 2-adrenergic receptor antagonist. Using the protocol mentioned above, 40 µg kg-1 min-1 dopamine was infused for 10 min and was followed by yohimbine (3 mg kg-1) that was followed 5 min later by a repeat of the dopamine infusion. A68930
[GenBank]
hydrochloride (50 µgkg-1 min-1) and (-)-quinpirole (50 µg kg-1 min-1) were also both challenged with yohimbine (3 mg kg-1).
Data Analysis
The peak effects of electrical stimulation and dopamine infusion on dural vessel diameter was calculated as a percentage change from the prestimulation baseline diameter. The nature of the experimental setup, where the magnification of the dural vessel selected for study was different in each setup, made it impractical to standardize the dural vessel measurement; therefore, the dural vessel diameter was measured in arbitrary units, and all calculations are related to the premanipulation baseline. The vessel size was approximately 150 to 200 µm. All data are expressed as mean ± S.E.M. Statistical analysis was performed using an ANOVA for repeated measures with Bonferroni's post hoc correction for multiple comparisons followed by Student's paired t test where appropriate (SPSS version 10.0; SPSS Inc., Chicago, IL). Significance was assessed at the P < 0.05 level or below. The reproducibility of the neurogenic vasodilator response has been tested previously using four consecutive saline-controlled stimuli (Akerman et al., 2002) in the same experimental setup.
Drugs
Dopamine was purchased as dopamine hydrochloride predissolved in water for injection (Faulding Pharmaceuticals Plc, Warwick, UK). R-(+)-SCH-23390 hydrochloride, S-(-)-eticlopride hydrochloride [S-(-)-3-chloro-5-ethyl-N-([1-ethyl-2-pyrrolidinyl]methyl)-6-hydroxy-2-methoxybenzamide hydrochloride], U99194A maleate, and L-745,870 hydrochloride (each in a 10 mg ml-1 solution and all from Sigma Chemical, Poole, Dorset, UK) were dissolved in water for injection as salts and administered in an approximate volume of 0.3 ml. A68930
[GenBank]
hydrochloride and (-)-quinpirole hydrochloride [(4aRtrans)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline] (Tocris Cookson Inc., Bristol, UK) were dissolved in water for injection. There is a summary of drugs used in Table 1.
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Results |
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2-adrenergic receptor antagonist yohimbine (3 mg kg-1), 31.4 ± 8 compared with 72.5 ± 8% (t5 = 2.26, P = 0.073, n = 6), and by the D1 dopamine receptor antagonist R-(+)-SCH-23390 (1 mg kg-1), 31.4 ± 8 compared with 54.8 ± 10% (t5 = 4.4, P < 0.05, n = 6), although in each case the response was still significantly different. The dopamine hydrochloride response was not inhibited by the specific D2 dopamine receptor antagonist S-(-)-eticlopride hydrochloride (3 mg kg-1), 31.4 ± 8 compared with 35.0 ± 6% (t5 = 9.99, P < 0.05, n = 6) (Fig. 1B). The A68930
[GenBank]
hydrochloride-induced inhibition of neurogenic dural vasodilatation was also reversed by yohimbine (3 mg kg-1), 24.49 ± 9% compared with 102.6 ± 4% (t4 = -6.15, P < 0.05, n = 5) (Fig. 2).
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Effect of Dopamine Hydrochloride and D1 and D2 Receptor Agonists on Dural Blood Vessel Diameter and Mean Arterial Blood Pressure. In rats treated with dopamine hydrochloride (0.5, 1, 2, 5, 10, 15, 20, and 40 µg kg-1 min-1), there was no significant effect on dural vessel diameter across all doses using an ANOVA for repeated measures (F7,35 = 1.423, P = 0.288, n = 6), although using a Student's paired t test both the 20 (t16 = 3.8, P < 0.05) and 40 µg kg-1 min-1 (t39 = 7.9, P < 0.05) doses were significant in all animals tested (Table 3). The slight change in dural blood vessel diameter was accompanied by a significant increase in blood pressure across all doses (F7,35 = 16.667, P < 0.0001, n = 6). The blood pressure change at the 15 µgkg-1 min-1 (t5 = 3.427, P < 0.05), 20 µgkg-1 min-1 (t16 = -6.15, P < 0.05), and 40 µg kg-1 min-1 (t39 = -11.62, P < 0.05) doses were significant compared with the preinjection blood pressure (Table 3).
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A68930 hydrochloride (1, 10, and 50 µg kg-1) did not cause any significant change in the dural blood vessel diameter across the cohort (F2,10 = 2.3, P = 0.175, n = 6); however, using Student's paired t test, both 10 (t5 = 4.5, P < 0.05) and 50 µg kg-1 (t13 = 3.85, P < 0.05) proved significant in all animals tested. There was a significant change in arterial blood pressure overall (F2,10 = 27.6, P < 0.05, n = 6). The blood pressure change with the 50 µg kg-1 dose of A68930 [GenBank] hydrochloride proved to be significant (t13 = -7.88, P < 0.05). (-)-Quinpirole hydrochloride (1, 10, and 50 µg kg-1) did not cause any significant change in both dural blood vessel diameter (F2,10 = 0.381, P = 0.63, n = 6) or arterial blood pressure (F2,10 = 2.78, P = 0.137, n = 6); these data are summarized in Table 4.
Effects of Dopamine Receptor Antagonists and an 2-Adrenergic Receptor Antagonist on Blood Vessel Diameter and Mean Arterial Blood Pressure Changes Caused by Dopamine. The effects of 40 µg kg-1 min-1 dopamine were challenged with various dopamine receptor antagonists. When the effects of 40 µg kg-1 min-1 dopamine on vessel diameter were compared with the preinjection diameter, there was a significant drop in diameter (t24 = 5.619, P < 0.001, n = 25). R-(+)-SCH-23390, the D1 receptor antagonist, had no significant effect on the dopamine-induced changes to dural blood vessel diameter (F2,10 = 1.0, P = 0.37, n = 6). The dopamine-induced blood pressure changes were significantly reduced with R-(+)-SCH-23390 compared with the control response (F2,10 = 6.451, P = 0.029, n = 6). With the 1.0 mg kg-1 dose of R-(+)-SCH-23390, there was a 46.2 ± 6 compared with 34.1 ± 6 mm Hg decrease in mean arterial blood pressure (t5 = 3.05, P = 0.028, n = 6).
S-(-)-Eticlopride hydrochloride, the D2 receptor antagonist, had no significant effect on the dopamine-induced changes in dural blood vessel diameter (F3,18 = 0.282, P = 0.682, n = 7) or mean arterial blood pressure (F3,18 = 3.857, P = 0.06, n = 7).
U99194A maleate, the D3 receptor antagonist, had no significant effect on the dopamine-induced changes in dural blood vessel diameter (F2,10 = 1.404, P = 0.292, n = 6) or mean arterial blood pressure (F2,10 = 1.401, P = 0.292, n = 6). Finally, in rats treated with L-745,870 hydrochloride, the D4 receptor antagonist, there was no significant effect on the dopamine-induced changes in dural blood vessel diameter (F2,12 = 0.279, P = 0.719, n = 7) or mean arterial blood pressure (F2,12 = 0.714, P = 0.448, n = 7).
Yohimbine (3 mg kg-1), the 2-adrenergic receptor antagonist, was able to significantly attenuate the dural blood vessel changes caused by 40 µg kg-1 min-1 dopamine infusion, from a 22.2 ± 4 to a 3.3 ± 2% reduction in vessel diameter (t6 = 4.73, P < 0.05, n = 7). The mean arterial blood pressure changes caused by dopamine infusion were also significant, reduced from 29.3 ± 7 to 2.7 ± 2 mm Hg (t6 = 3.54, P < 0.05, n = 7).
The effects of the D1 and D2 dopamine receptor agonists were also challenged with yohimbine (3 mg kg-1). Yohimbine did not alter the response of A68930 [GenBank] hydrochloride (50 µg kg-1 min-1) on dural blood vessel diameter (t5 = 1.42, P = 0.214, n = 6), but it was able to reverse the arterial blood pressure effects from a 40.2 ± 4 mm Hg increase to a 10.7 ± 3 mm Hg increase (t5 = 5, P < 0.05, n = 6). Yohimbine did not alter the response of (-)-quinpirole hydrochloride (50 µg kg-1 min-1) on dural blood vessel diameter (t4 = 0.23, P = 0.828, n = 5) and arterial blood pressure (t4 = 0.19, P = 0.86, n = 5) (Table 4).
Effects of Dopamine Antagonists and an 2-Adrenerngic Receptor Antagonist on Dural Blood Vessel Diameter and Mean Arterial Blood Pressure. The data for the changes caused by the dopamine receptor antagonists on dural blood vessel diameter and mean arterial blood pressure are summarized in Table 5. Briefly, the D1 receptor antagonist R-(+)-SCH-23390 significantly increased blood pressure, and this increase was accompanied by a significant decrease in dural vessel diameter. S-(-)-Eticlopride hydrochloride, the D2 receptor antagonist only caused a significant change in blood pressure at the 3 mg kg-1 dose, and there was no significant change to dural vessel diameter. The D3 receptor antagonist U99194A maleate significantly increased blood pressure at all doses, but only altered dural vessel diameter at the 1.0 mg kg-1 dose. Finally, L-745,870 hydrochloride, the D4 receptor antagonist, significantly decreased blood pressure at the 1 and 3 mg kg-1 doses, but only affected the dural blood vessel diameter at the 1 mg kg-1 dose.
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Yohimbine, the 2-adrenergic receptor antagonist, caused a significant reduction in mean arterial blood pressure of 34.4 ± 5 mm Hg (t12 = 7.51, P < 0.05, n = 13); this reduction was accompanied by a significant 52.4 ± 18% increase (t12 = 3.41, P < 0.05, n = 13) in dural blood vessel diameter. Both were naturally restored to their preinjection levels within the time constraints of the experimental protocol.
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Discussion |
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). Given that apomorphine, the dopamine receptor agonist, exacerbates yawning during the migraine attack (Blin et al., 1991), and domperidone, the D2 dopamine receptor antagonist, blocked nausea and vomiting caused by piribedil (Bes et al., 1986), we chose to antagonize dopamine receptors during neurogenic dural vasodilation. The D1, D2, D3, and D4 dopamine receptors were all unable to inhibit or attenuate neurogenic dural vasodilation.
By administering dopamine hydrochloride and A68930
[GenBank]
hydrochloride, the D1 receptor agonist, we were able to attenuate neurogenic dural vasodilation. Upon cessation of dopamine agonist infusion, repeat electrical stimulation was able to produce a maximum neurogenic vasodilation. In each case, this effect was partly antagonized by the 2-adrenoceptor antagonist yohimbine. The dopamine hydrochloride response was also partially attenuated by the D1 receptor antagonist SCH-23390, although the antagonized response was still significantly less than the control neurogenic dural vasodilation. The D2 receptor agonist had no effect on neurogenic dural vasodilation. The ability of dopamine hydrochloride to attenuate neurogenic dural vasodilation may in part be explained by the vasoconstrictive effect of dopamine, which we believe to be caused as a response to the profound blood pressure changes. We have established already, and it has been shown previously, the vasoconstriction and blood pressure changes seem to be mediated by a noradrenergic response at the 2-adrenoceptor (Edvinsson et al., 1978a,b; Willems et al., 1999; Villalon et al., 2003). It therefore seems that some of the inhibition is mediated by the 2-adrenoceptor. It is possible that the D1 dopamine receptor may contribute to this effect given the response of the agonist and antagonist in this model. The D1 dopamine receptor antagonist was unable to fully inhibit the effects of the dopamine-induced inhibition; therefore, we describe a clear but partial response. The D1 receptor agonist's attenuation of neurogenic dural vasodilation was almost fully inhibited by 2-adrenoceptor modulation; therefore, any action of dopamine agonists will be compromised by 2-adrenoceptor activation and blood pressure effects. The partial D1 dopamine receptor component in this model of trigeminovascular nociception may explain the actions of some migraine preventives that are known to act on dopamine receptors (Peroutka, 1997; Mascia et al., 1998; Fanciullacci et al., 2000).
Neurogenic dural vasodilation is thought to result from the presynaptic release of CGRP from trigeminal nerve terminals acting on CGRP receptors on the dural blood vessels, causing vasodilation (Williamson et al., 1997b). The data presented suggest that D1 dopamine receptors may be involved in the control of the dural vasculature on trigeminal nerve endings. It has been shown previously that there is a lack of response on neurogenic dural vasodilation when 2-adrenoceptors are manipulated (Akerman et al., 2001); therefore, it seems unlikely that dopamine is activating through prejunctional 2-adrenoceptors to exert its inhibitory action in the trigeminovascular system. There is evidence that D2 dopamine receptors are present in the trigeminal ganglion, using a cDNA probe and hybridization techniques (Peterfreund et al., 1995), although from the data they may not be transported to peripheral trigeminal nerve endings, so that antagonizing these receptors did not affect A
-trigeminal nerve activation and neurogenic dural vasodilation. It seems that the majority of the inhibitory response is mediated by the 2-adrenoceptor effect on mean arterial blood pressure, but there is a minor, significant response mediated by D1 dopamine receptors.
The use of yohimbine as the 2-adrenoceptor antagonist may seem odd given its action at other receptors relevant in this system, 5-HT1A/1B/1D agonist and D2 and D3 antagonist (Millan et al., 2000). However, we have shown previously that the 2-adrenoceptor is not involved in neurogenic dural vasodilation (Akerman et al., 2001). 5-HT1B/1D receptors have been shown previously to inhibit the neurogenic response (Williamson et al., 1997b), the dose of yohimbine is not sufficient to inhibit these neurons. Yohimbine is able to actively inhibit 2-adrenoceptor agonist effects at this dose (Hsu and Kakuk, 1984; Liu and Coupar, 1997). There is little evidence of a 5-HT1A effect in the trigeminovascular system (Cumberbatch et al., 1998). Finally, from evidence taken from the data presented here, neither D2 nor D3 receptors have any effect on either dopamine-induced vasoconstriction changes or on neurogenic dural vasodilation. It was also found that D2 receptor antagonists were unable to reverse the dopamine inhibition of neurogenic dural vasodilation, and given that D3 receptors are considered D2-like, we tentatively conclude that yohimbine effects are 2-adrenoceptor-specific.
As reported in pial, cerebral, and carotid arteries (Edvinsson et al., 1978a,b; Villalon et al., 2003), increasing doses of dopamine caused a vasoconstriction in the dural meningeal arteries. This was significant at the highest doses given in this study, but other studies have used higher dosing regimens. We were primarily interested in a vasodilatory response and only found a significant vasodilation at the 1 µg kg-1 min-1 dose regimen. We observe that at a lower dose, there was no significant dilation and at higher doses we found increasing vasoconstriction, similar to other studies.
It was unexpected that the vasodilatory effect was not clearly dose-dependent, and the vasodilation was not as extensive as that found in other in vivo studies. Indeed vasodilation has been found at much higher doses, also using an intravenous method of entry (Villalon et al., 2003; Polakowski et al., 2004). Villalon et al. (2003) only found a vasodilator effect with dopamine hydrochloride in the presence of a 2-adrenoceptor antagonist; we saw no vasodilator effect in the presence of yohimbine in the dural circulation. Previous studies have also shown that a specific D1 receptor agonist, fenoldopam, was able to cause vasodilation on its own (Villalon et al., 2003; Polakowski et al., 2004). In our study, the specific D1 receptor agonist caused a significant vasoconstriction in dural blood vessel caliber and a significant increase in arterial blood pressure. These changes were reversed by an 2-adrenoceptor antagonist. The D2 receptor agonist was unable to significantly alter either blood vessel diameter or mean arterial blood pressure. We conclude that the changes observed in the dural blood vessels and arterial blood pressure are mediated by vascular 2-adrenoceptors rather than dopamine receptors.
Dopamine acts as a precursor to the catecholamines noradrenaline and adrenaline, which mediate vasoconstriction and blood pressure increase through the 1 and 2-adrenoceptors (Willems et al., 1999). In the present study, dopamine is likely to be acting as a precursor to noradrenaline in this biological system and thus activating the noradrenergic system to cause vasoconstriction and blood pressure increase. Only the 1 mg kg-1 dose of the D1 dopamine receptor antagonist was able to attenuate the blood pressure increase, but there was still a significant blood pressure increase. The 2-adrenoceptor antagonist was able to reverse both the vasoconstriction and the blood pressure changes caused by the highest dose of dopamine hydrochloride.
The action of the dopamine agonist fenoldopam caused mean arterial blood pressure decrease accompanied by a vasodilation (Polakowski et al., 2004), which conflicts with the findings of A68930
[GenBank]
hydrochloride used in the present study, wherein only vasoconstriction was inhibited by the 2-adrenoceptor antagonist. This is similar to the effects of dopamine hydrochloride. The differences in the response of the specific dopamine agonists may represent a difference in their abilities to activate noradrenergic production. It would certainly be interesting to observe the affects of fenoldopam in the system used in this study.
Significant blood pressure changes were caused by all dopamine receptor antagonists at varying doses, and these were variously accompanied by a change in dural blood vessel diameter. Given the role of dopamine as a precursor of both noradrenaline and adrenaline, and given that amines are released to maintain vascular tone, it is possible that the effect of the dopamine antagonists on blood pressure are a response to inhibition of the precursor to adrenergic synthesis, namely, dopamine, and the dural blood vessel diameter changes are a response to the change in blood pressure. This seems to be indicated by the lack of inhibitory effect of the dopamine receptor antagonists on dopamine hydrochloride-induced changes, whereas the 2-adrenoceptor antagonist had profound inhibitory effects.
Despite the evidence that dopamine receptors may be present in the trigeminovascular system (Peterfreund et al., 1995) and that dopamine agonists have been found to exacerbate certain types of headache (Levy et al., 2003), only the D1 receptor is able to attenuate or inhibit the activation of dural blood vessels or trigeminal neurons, and this response was only a partial effect, suggesting perhaps a small role in the acute phase of migraine. There were other effects, perhaps due to vasoconstriction caused by activation of the 2-adrenoceptor. The involvement of dopamine and its receptors in migraine may dominate in other aspects of the attack, such as the initiation, providing a role for dopamine modulators in short or long-term prevention.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CGRP, calcitonin gene-related peptide; 5-HT, 5-hydroxytryptamine (serotonin); R-(+)-SCH-23390, (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; U99194A, 5,6-dimethyoxy-2-(di-n-propylamino)indan; L-745,870, 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolol(2,3-b)pyridine; A68930 [GenBank] , cis-(±)-1-(aminomethyl)-3,4-dihydro-3-phenyl-1H-2-benzopyran-5,6-diol; ANOVA, analysis of variance; NDV, neurogenic dural vasodilation.
Address correspondence to: Professor P. J. Goadsby, Institute of Neurology, Queen Square, London, WC1N 3BG UK. E-mail: peterg{at}ion.ucl.ac.uk
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