The effect of anti-migraine compounds on nitric oxide-induced dilation of dural meningeal vessels

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Abstract

Migraine is characteristically accompanied by a throbbing quality of head pain thought to involve trigeminovascular afferents. Administration of nitric oxide (NO) donors provides the most reliable model of migraine induction in humans. The present studies used intravital microscopy to monitor the effect of local meningeal nerve stimulation and NO on dural blood vessels and any modulation of that effect by anti-migraine compounds. NO caused an immediate and reproducible dilation of meningeal blood vessels that was partially blocked by sumatriptan and indomethacin, while flunarizine and histamine H1 and H2 receptor antagonists were unable to block the dilation. Indomethacin also inhibited the neurogenic dilation while flunarizine did not. The present studies demonstrate that NO is unlikely to interact with histamine to produce its dilatory response. Sumatriptan and indomethacin inhibit the NO response by inhibiting trigeminal activation and calcitonin gene-related peptide (CGRP) release. Flunarizine does not modify either the neurogenic vasodilator response or the NO meningeal dilator response at least acutely.

Introduction

Migraine is characteristically accompanied by a throbbing quality of head pain whose pathophysiology, although not fully understood, is thought to include activation of trigeminal afferents (Goadsby et al., 2002). The mechanism of action of anti-migraine compounds, or compounds that trigger attacks, is of interest in the context of developing new treatment strategies. Williamson et al. (1997a) developed an intravital microscopy technique that allows continual observation of dural blood vessels so any changes in meningeal vessel diameter during intravenous administration of drugs can be observed. This technique also allows direct observation of changes in meningeal vessel diameter during dural electrical depolarisation of trigeminal fibres known in humans to be pain-producing (Wolff, 1948), providing a means of studying trigeminovascular dural pharmacology in vivo.

Nitric oxide (NO) is a potent endogenous vasodilator with an impressive array of biological actions (Moncada et al., 1991). NO causes headache and migraine in both control volunteers and headache patients, and will also cause a delayed headache that fulfils The International Headache Society criteria for migraine (Headache Classification Committee of The International Headache Society, 1988) in sufferers several hours after the NO infusion Iversen et al., 1989, Olesen et al., 1993, Olesen et al., 1994. NO-induced migraine can be prevented or alleviated by certain established anti-migraine compounds. In nonmigraineurs, NO-induced headache is attenuated by sumatriptan when administered prior to the NO infusion (Iversen and Olesen, 1996). Sumatriptan also inhibits the regional cerebral blood flow increase that was found in the rat to NO donor infusion (Read et al., 1999), although changes in cerebral blood flow itself are not seen in humans with NO donor infusion (White et al., 2000).

Compounds clinically effective against acute migraine, such as 5-HT1B/1D receptor agonists Williamson et al., 1997a, Williamson et al., 1997b, Williamson et al., 2001a, and μ-opioid receptor agonists (Williamson et al., 2001b) can inhibit neurogenic meningeal dural vasodilatation caused by electrical stimulation. This action is thought to be via inhibition of the release of calcitonin gene-related peptide (CGRP) from trigeminal sensory fibres innervating the cranial blood vessels (Williamson and Hargreaves, 2001). Indomethacin is a nonsteroidal anti-inflammatory drug that is believed to act by inhibiting cyclooxygenase activity that helps produce prostaglandins (Abdel-Halim et al., 1978). It is helpful for some migraineurs and inhibits NO-induced headache (Castellano et al., 1998). However, its mechanism of action in migraine is not completely clear. Flunarizine, a migraine preventative (Leone et al., 1991), whose migraine action may involve inhibition of Ca2+ entry across the cell membrane (Geer et al., 1993), may interact with NO generation mechanisms. Flunarizine reduced the relaxation found with electrical stimulation of intramural nerve terminals of arterial strips while relaxation by NO or sodium nitroprusside (NO donor) was not inhibited by flunarizine (Ayajiki et al., 1997).

The purpose of this study was to examine the effects that NO has on dural blood vessel diameter using the intravital microscopy and the effect of anti-migraine compounds given as either a pretreatment or a treatment during the NO response. Histamine infusion can cause headache in humans Krabbe and Olesen, 1980, Lassen et al., 1995, and the relationship it has with NO is certainly important. Therefore, we applied histamine receptor antagonists to compare and contrast effects in this model with results seen in clinical studies. Finally, we examined the effect of indomethacin and flunarizine on the neurogenic dural vasodilatation since sumatriptan inhibits this response (Williamson et al., 1997a).

Section snippets

Surgical preparation

Male Sprague–Dawley rats (300–400 g) were anaesthetised throughout the experiments with sodium pentobarbitone (60 mg/kg i.p. and then 18 mg/kg/h i.v. infusion). The left femoral artery and vein were cannulated for blood pressure recording and intravenous infusion of anaesthetic, respectively. Temperature was maintained throughout using a homeothermic blanket system. The rats were placed in a stereotactic frame, the skull exposed and the right parietal bone thinned by drilling with a

Effects of a nitric oxide donor and electrical stimulation on dural vessel diameter

Sodium nitroprusside produced an increase in vessel diameter of 104±7% (n=29) for the length of the infusion (15 min) as a total across all experiments (Fig. 1). This was accompanied by a decrease in arterial blood pressure that returned to normal after the infusion. In the control studies with sodium nitroprusside, the mean dilations were 100±8%, 103±5%, 87±3% and 87±10%, respectively (n=6). There was no difference across the cohort (F (3, 15)=1.756, P=0.199). In the control studies, four

Discussion

Nitric oxide (NO) is able to cause vasodilation of cranial blood vessels by relaxing smooth muscle tissue through a decrease in intracellular Ca2+ (Moncada et al., 1991), and this study shows that NO was able to cause dilation of meningeal blood vessels when injected into the carotid artery. This study also demonstrates that indomethacin can inhibit electrically evoked vasodilation, similar to that found previously with sumatriptan (Williamson et al., 1997a). We observed no effect of either

Acknowledgements

The authors would like to thank the Pharmacology Group at Merck and Thorsten Bartsch, Yolande Knight and Paul Hammond of the Headache Group at the Institute of Neurology for both assistance and technical support during these experiments. This work has been supported by the Wellcome Trust. PJG is a Wellcome Senior Research Fellow.

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