Brain, Vol. 122, No. 2, 369-370,
February 1999
© 1999 Oxford University Press
Book Reviews |
HEADACHE PATHOGENESIS. Volume 7.MONOAMINES, NEUROPEPTIDES, PURINES, AND NITRIC OXIDE.
By Jes Olesen and Lars Edvinsson.1997. Pp. 352. Philadelphia: Lippincott-Raven.Price £72.50. ISBN 7-7817-1208-4..
Department of Clinical Neurosciences, King's College School of Medicine and the Institute of Psychiatry, London, UK
The aim of this book is to bring together available knowledge, much of it recent, about messenger molecules and their receptors involved in primary headaches. Individual chapters are summaries of platform presentations or posters presented at a recent international headache research seminar. These are divided into sections covering messenger molecules in relation to the blood vessels themselves, the role of such molecules in pain processing and the evidence linking amines and amino acids, neuropeptides and nitric oxide (NO) respectively, in the pathogenesis of migraine.
The first messenger molecule to be implicated in migraine was 5-hydroxytryptamine (5-HT). Blood 5-HT levels decrease during a migraine attack and this prompted the search for 5-HT receptor antagonists and agonists as possible therapeutic agents. This has culminated in the development of sumatriptan, an effective therapy for acute migrainous attack. While 5-HT is important in the pathogenesis of migraine this is by no means the whole story, and even the action of drugs such as sumatriptan may be more complicated than first thought.
Many of the chapters focus on the potential role of NO in migraine pathogenesis. This hypothesis is well developed by Olesen and colleagues who base it on three main lines of evidence. Firstly, activation of the NO–cGMP pathway causes migraine attacks in migraineurs. Second, drugs that are effective in the treatment of migraine, and that are not general analgesics, exert their activity by inhibiting one or more steps in the NO pathway. Third, substances that are able to precipitate an attack of migraine do so by stimulating one or more steps in the NO pathway.
It has been appreciated for many years that the NO donor glyceryl trinitrate (GTN) can cause headache. More recently, as covered in a number of the chapters, it has been appreciated that in migraineurs GTN produces both a more severe immediate headache, and in a high proportion a delayed headache with peak intensity at about five and a half hours. This delayed headache is only seen in migraineurs. GTN results in dilatation of both extracranial and intracranial vessels and this dilatation appears to be greater in migraineurs, Therefore, the initial headache following GTN could result from intracranial arterial vasodilatation and subsequent perivascular nerve stimulation. However, this would be unable to account for the delayed headache. It has been suggested that this may be secondary to a sterile inflammatory response, but in the chapter by Martelletti and colleagues no activation of inflammatory mechanisms, including intracellular adhesion molecules and cytokines was found. It is possible that NO at an early stage could sensitize perivascular sensory nerves. Normally in situations where a transmitter increases there is counter regulation or desensitization, but some evidence suggests that a brief infusion of GTN may induce not only an immediate peak of NO in the cerebral cortex, but also a delayed and protracted increase. A further strand tying NO to migraine is cortical spreading depression. This has been implicated in migraine and a study by Parsons shows that it results in marked NO release.
In Olesen's chapter, and in others, mechanisms are given by which conventional anti-migraine drugs could exert their effect via NO release. Some of these are more convincing than others. Interestingly, it is reported that sumatriptan in arterial homogenates can down-regulate the activity of nitric oxide synthase (NOS) suggesting sumatriptan could be acting partly through NO antagonism. Possible mechanisms via which oxygen, calcium antagonists and propanolol may exert their action via the NO system are also suggested. If NO is indeed important, one might expect that inhibition of NOS would abort migraine attacks. Testing of this hypothesis is described. The non-isoform specific inhibitor Ng methyl-L-arginine hydrochloride (L-NMMA) was given to patients with acute migraine. It resulted in a significantly lower headache score at 1 h. However, interpretation is complicated by the fact that most of the controls were historical controls from previous studies rather than randomized on a double-blind basis. This is a common problem with a number of the studies described in this book which have been poorly controlled, making interpretation of the significance of the findings difficult. Similarly, interpretation is sometimes made difficult by poor study design. For example, It is possible that the effect of L-NMMA on migraine could be a non-specific action secondary to its vasoconstrictor effect. It was argued that this was unlikely because in another study described in the book L-NMMA had no effect on middle cerebral artery blood flow velocity; it was therefore implied that it has no effect on middle cerebral artery diameter. However, transcranial Doppler measures only velocity and therefore if both diameter and velocity decrease to a similar degree no overall change in velocity will be seen despite a diameter reduction. Recent studies not described here suggest that this is indeed the case with L-NMMA.
Nevertheless, despite these criticisms, there appears to be much evidence to suggest that NO may indeed play an important role in the pathogenesis of migraine. If this were the case the well known familial tendency seen in migraine might be accounted for partly by inherited abnormal NO responses. However no evidence of a systemic vascular abnormality could be found; no alteration in radial artery vessel diameter during hyperaemia (induced by inflating and then deflating a brachial artery blood pressure cuff) could be found between migraineurs and normal controls. This flow-mediated vasodilatory response is mediated via NO release from endothelial NOS. There is obvious interest now in looking at the relationship between the three forms of NOS, endothelial, neuronal and inducible, and migraine. Currently drugs such as L-NMMA are non-isoform specific but there is intense interest in developing specific inhibitors of particular NOS isoforms for application in many fields including acute stroke; testing of these in patients with migraine will be interesting.
The papers in this book give an up to date account of many interesting findings relating to monoamines, neuropeptides, particularly calcitonin related gene peptide, the purines and NO in the pathogenesis of migraine. One can immediately appreciate the many potential steps at which the process could be interrupted with new anti-migraine drugs. However, the quality of the chapters does vary from excellent reviews such as on the role of non-opioid peptides in migraine and cluster headache, and the NO hypothesis of migraine, to others in which conclusions are difficult to draw, due either to experimental design weaknesses or a failure to set the author's individual findings in a more general context. To some extent this latter problem is overcome by a summary at the end of each section covering the discussion sessions held at the meeting. However, it could still be difficult for someone new to this area to determine the significance of individual papers. For this reason the book is more suitable for a reader with an already established interest in migraine pathogenesis, rather than as an introduction for the novice.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||