Abstract
In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP) but not with any of the other neuronal messengers. The purpose of this review is to describe the role of CGRP in the intracranial circulation and to elucidate a possible role for a specific CGRP receptor antagonist in the treatment of primary headaches. Acute treatment with a 5-HT1B/1D agonist (triptan) results in alleviation of the headache and normalization of the cranial venous CGRP levels, in part due to a presynaptic inhibitory effect on sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists with few cardiovascular side-effects. The initial pharmacological profile of such a group of compounds has recently been disclosed. One of these compounds has been found to be efficacious in the relief of acute attacks of migraine.
Introduction
The functional studies crucial to any hypothesis regarding headache rests on the classic observations of Ray and Wolff (1) who described painful sensations that resulted from mechanical or electrical stimulation of large cerebral arteries, venous sinuses, and dural arteries. The pain-sensitive supratentorial structures (but not subtentorial elements) are supplied by nerve fibres from the trigeminal ganglion, and there have been uncontrolled positive studies of the efficacy of retrogasserian rhizotomy of the trigeminal ganglia in migraine (2). A role of the trigemino-cerebrovascular system in the transmission of nociceptive information to the central nervous system is thus a viable proposition. Antidromic or local mechanical stimulation of sensory nerve endings results in vasodilatation of peripheral vessels via the release of vasoactive materials such as substance P and calcitonin gene-related peptide (CGRP) (3, 4). This vasomotor effect of the sensory nerves in the periphery appears to have a counterpart in the cerebral circulation with the trigeminal system. The cell bodies are located in the trigeminal ganglion, they send sensory fibres to various cranial structures, and connects to the CNS via the trigeminal nerve. The fibres and the cell bodies contain a number of messengers but CGRP is the one most frequently expressed (5).
CGRP immunoreactivity in intracranial vessels was first shown in 1984 (6), and subsequently found to originate in perikarya within the trigeminal ganglia of all species examined, including man (7). CGRP is frequently colocalized in trigeminal neuronal cells with substance P, neurokinin A, pituitary adenylate cyclase activating peptide (PACAP), amylin, neuronal nitric oxide synthase (NOS), although the number of CGRP-containing cells well exceeds the number of the others (5). Four sources of cerebrovascular CGRP have been described:
the ophthalmic division of the trigeminal ganglion, to innervate the circle of Willis and its branches by the nasociliary nerve;
the maxillary division, probably via an extradural branch at the skull base to the internal carotid artery;
the internal carotid miniganglia, via the greater deep petrosal nerve to distribute in the internal carotid artery and distribute proximally in its intracranial ramifications;
in the upper cervical dorsal root ganglia (C1–C3) to innervate the caudal third of the basilar artery and the vertebral artery (7–16).
The major cerebral arteries (anterior, middle, and posterior cerebral arteries, vertebral and basilar arteries) and pial arterioles of the cortical surface are invested with fine varicosed nerve fibres that contain CGRP (17). These nerve fibres are present in the adventitia and at the adventitial-medial border of the blood vessels and colocalized in the cerebrovascular nerve fibres with substance P (18, 19), neurokinin A (20), PACAP (8), NOS (8, 21), amylin (22) and nociceptin (23).
CGRP is a 37 amino acid peptide that results from alternative splicing of calcitonin gene transcripts (24). It exists in two forms α– and β– CGRP (25), which show considerable homology with amylin and adrenomedullin. The receptors belong to a family of G-protein coupled receptors that are linked to adenylate cyclase with diverse biological functions both in the peripheral and in the central nervous systems (4, 26, 27). CGRP containing nerves innervate blood vessels in most regions, the peptide is a potent vasodilator that is involved in pain processes (18, 19, 28). The physiological role of CGRP in the brain and in the cardiovascular system is in many pathological states not well understood (26, 27).
In one particular vascular region, the cerebral circulation, there is a particularly dense supply of trigeminal CGRP containing nerve fibres (18, 19). These fibres release CGRP following electrical stimulation (29–32) or administration of capsaicin (33–35) and are activated in primary headaches and in stroke (31, 36–40). Trigeminal fibres mediate dilatation of brain (17, 41–43), meningeal and dural vessels (43–48), mediate increases in cerebral blood flow (32), has no tonic influence on cerebral blood flow or metabolism (49) and has a key role in the trigeminovascular reflex (19, 33, 50). Although CGRP has a number of effects, its most pronounced action is that of vasodilatation (4, 28). The trigeminovascular system has a primary involvement in cranial sensory functions, but also acts as a vasodilator pathway involving antidromic release of the above signal substances but it is still only for CGRP that a functional role has been defined (19, 33, 50, 51).
Neurotransmitter release in primary headaches
The role of the sensory nerves around the intracranial vessels in primary headaches has been elucidated by analysis of neurotransmitter release in man: Activation of the trigeminal ganglion resulted in unilateral blood flow increases, CGRP and substance P release, and facial flushing on the side of stimulation (29).
Migraine
In migraine attacks there are both vascular and neurogenic components (36). Many consider that the disorder is due to mutations in a calcium channel gene rendering neurons unstable and capable of initiating a migraine attack in, e.g. stress; however, it has only been proven for familiar hemiplegic migraine (52). As part of the pathophysiological mechanisms the trigeminovascular system is activated and there is an antidromic release of CGRP, activation of neurons in the TNC with subsequent mediation of pain. The results from trigeminal ganglion stimulation in trigeminal neuralgia patients (neuropeptides are released and can be measured in the jugular vein) led us to examine during the migraine attacks the levels of neuronal messenger molecules (neuropeptides) associated with the autonomic and sensory nerves (29). The concentration of neuropeptide Y (NPY) (marker for the sympathetic nerves), vasoactive intestinal peptide (VIP) (parasympathetic activity), CGRP and substance P (both markers for sensory nerves) were analysed in the cranial venous outflow from the external jugular vein (Table 1). There were no changes in the levels of NPY, VIP or substance P. However, a marked increase in CGRP was observed during migraine headache (37). Two individuals with facial symptoms similar to those seen in cluster headache (e.g. nasal congestion and rhinorrhea), displayed in addition increases in VIP. This suggests the involvement of a parasympathetically mediated event in these two individuals. There was no difference between patients with attacks of migraine with aura or without aura; each subject had marked CGRP release.
Overview of changes in perivascular neuropeptide levels occurring in acute attacks of primary headache disorders
± 0, no change from before headache;
significant increase in neuropeptide level.
The release of CGRP rather than substance P is due to the fact that the cerebral circulation is innervated by CGRP-containing fibres from the trigeminal ganglion (7, 13, 14, 53). These initial clinical observations have been confirmed in subsequent studies in man (31, 54). In addition, following sumatriptan administration, the plasma levels of CGRP returned to control with successful amelioration of the headache (31). The 5-HT1B/1D receptors are expressed on trigeminal ganglion cells of man (55) and guinea pig (56) and on human trigeminal sensory fibres (57, 58) thus providing sites for presynaptic inhibition of the CGRP release. Durham and Russo (59, 60) have examined this in detail and shown that sumatriptan causes a markedly prolonged increase in intracellular calcium in trigeminal neurons which suggests potential mechanisms involved in the inhibition of CGRP release.
Cluster headache
Cluster headache is a well-described clear–cut clinical syndrome. Patients with episodic cluster headache, fulfilling the criteria of the International Headache Society, were examined during acute spontaneous attacks of headache to determine the local cranial release of neuropeptides (38). During the attacks, the blood levels of both CGRP and VIP were markedly raised while there was no change in NPY or substance P (Table 1). Treatment with oxygen or subcutaneous sumatriptan aborted the pain and normalized the CGRP levels, while opiate administration did not alter the peptide levels. The results show that activation of the cranial sensory and parasympathetic nerves have a role in acute attacks of cluster headache. It was particularly noteworthy that all subjects responded with release of VIP, being in concert with the extracranial symptoms.
The results are in excellent agreement with those of others, who have shown release of CGRP in nitroglycerine-elicited attacks of cluster headache (38, 61, 62). CGRP was elevated during the attack period and was elevated further at the peak of the provoked attack. There was no alteration in substance P levels. Interestingly, only when the subjects were in an active period was nitroglycerine able to elicit an attack of cluster headache (62). This suggests that the trigeminovascular system is hyperreactive at this stage.
Thus, CGRP, a marker of the trigemino-vascular system, and VIP, a marker of the parasympathetic nerve activity, are both elevated in acute spontaneous attacks of cluster headache. The attacks were terminated with either sumatriptan or oxygen and associated with normalized CGRP levels, reflecting cessation of the activity in the trigeminovascular system (38). The finding of elevated levels of both CGRP and VIP during attacks further suggests that there is activation of a brainstem reflex, the afferent arc of which is the trigeminal nerve and the efferent the cranial parasympathetic outflow from the VIIth nerve (30, 63, 64).
Trigeminal neuralgia
In a comparison of normal individuals and of subjects with trigeminal neuralgia (29), there was no alteration in the resting levels of neuropeptides. Stimulation of the trigeminal ganglion during thermocoagulation caused a marked increase in the blood levels of CGRP and substance P, and this was associated with unilateral facial flushing. After cessation of the stimulation, the peptide levels returned towards normal levels.
Vasoactive substances may be responsible not only in the mechanisms that cause headache but also in neuronally mediated facial flushing. This conclusion was supported by study of an unstable trigeminal system in which the pain attacks were associated with rhinorrhea and facial flushing (65). Conventional pharmacological therapy did not provide lasting relief and local facial stimulation by tapping a painful trigger point led to both pain and flushing (65), associated with a marked increase in CGRP levels during the flushing, but without any change in substance P, NPY or VIP.
Chronic paroxysmal hemicrania
Chronic paroxysmal hemicrania (CPH) is a rare syndrome that is defined by the IHS operational diagnostic criteria as frequent short-lasting attacks of unilateral pain usually in the orbital, supra-orbital or temporal regions that may last for 2–45 min (attack frequency, often five or more each day). The pain is associated with prominent autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, rhinorrhea, ptosis or eyelid oedema. According to the diagnostic criteria that the attacks should settle rapidly upon treatment with indomethacin.
In one such case, we observed that, during pain, the CGRP level rose 3-times compared to the level while the subject was on indomethacin. The VIP level increased 4 times during an attack and normalized upon indomethacin treatment (66). The case report and the accompanying data show that attacks of CPH are characterized by activation of both sensory and parasympathetic cranial nerve fibres. Thus, in this way CPH resembles cluster headache.
Responses to CGRP
CGRP is a potent cerebral vasodilator in all species tested (17). The relative potency of different forms of CGRP varies among species; in the cat middle cerebral artery all CGRP variants induce relaxation to the same degree and potency and much more than does substance P; in human cerebral arteries, the maximum responses to CGRP, substance P, and neurokinin A are similar, but CGRP induces relaxations at 100–1000 times lower concentrations. In general, CGRP is the most potent known vasoactive constituent of trigemino-vascular nerves, by far superseding substance P, neurokinin A, PACAP, amylin, galanin and dynorphine in efficacy and potency (Table 2). In addition, CGRP is about 25-fold more potent as a vasodilator of cerebral as compared to other cranial arteries (43, 67, 68). We interpret this phenomenon as due to the existence of a higher number of CGRP receptors in cerebral as compared to other arteries. This is supported by both histochemical data (69) and the modelling of receptor dynamics outlined by Black and Leff (70).
Potency (pEC50; pD2) and effiacy (Emax) of neuronal messengers found in the trigeminal ganglion of human cerebral (CMA) and middle meningeal arteries (MMA)
cat. Emax value, variation in different human studies; PD2, means from cited human studies(see text); Rel.pot, relative potency as compared to the value of substance P (SP) set as unity.
The relaxant effect of CGRP remains after removal of the endothelium, is paralleled by an increase in adenylate cyclase activity (71) and both effects are blocked by CGRP antagonists (34). CGRP induces a greater dilatation of pial arterioles in situ than substance P (19). Unlike substance P, CGRP does not provoke dilatation of pial veins when given abluminally. The pial arteriolar responses after a single application of CGRP are sustained for several minutes, particularly at high concentrations (19, 50). The potency of CGRP as a cerebrovascular dilator, its sustained action in vivo, its release by capsaicin, the lack of effect of neurokinin antagonists or nitric oxide synthase inhibitors while a CGRP blocker has effect, all point to the involvement of CGRP in the restoration of vascular calibre after vasoconstriction. To understand the role of CGRP released from perivascular nerves relative to circulating CGRP, we used the pressurized middle cerebral artery (MCA) method, a technique allowing discrete investigation of the relative contribution of endothelial and smooth muscle cells to vascular tone. MCAs from Sprague-Dawley rats were mounted onto two glass micropipettes, pressurized to 85 mmHg and luminally perfused. The diameter responses to luminally and abluminally applied α- and β-CGRP, adrenomedullin and amylin were compared relative to the resting diameter. Only abluminally administrated α- and β-CGRP showed significant dilatory effects, mediated through the CGRP receptor (72). The endothelial barrier in the pressurized arteriograph may mimic the in vivo situation preventing the peptides from reaching their receptors in the medial layer.
Some aspects on the activation of the trigeminovascular afferents have been studied using an intravital microscope preparation. Thus, electrical stimulation of the dura mater elicits dilatation of dural blood vessels, a response that is due mainly to the release of CGRP since it can be abolished by CGRP antagonists but not by neurokinin agonists or blockers (73). This and other data have pointed out that substance P is not involved in vascular nociception in man (74).
A recent study in man using SPECT to determine regional cerebral blood flow (rCBF) revealed that systemic infusion of CGRP had minor effects on rCBF (75, 76). Transcranial Doppler used in parallel to determine blood flux velocity in the MCA was seen to result in a reduction during the CGRP infusion, suggesting that CGRP dilated the MCA in vivo. This agrees well with studies in rat, guinea-pig and rabbit where at most minor effects were seen upon CGRP administration (77–79). Chronic surgical division of the trigeminal nerve in cats does not modify local cerebral blood flow, glucose utilization, or the magnitude of the arteriolar responses to perivascular microapplication of either vasconstrictor or vasodilatory agents (49) while stimulation results in local CBF increases that is blocked by a CGRP antagonist (31, 32, 80, 81). However, trigeminal lesion prolongs the duration of the cerebral arteriolar vasoconstriction induced by noradrenaline, prostaglandin F 2α, barium chloride, alkaline pH and blood without altering the duration of vasodilatatory responses (19, 50). The cerebrovascular trigeminal neuronal system, in which CGRP is the most potent vasoactive constituent, appears to be involved in a reflex or local response to excessive cerebral vasoconstriction that facilitates the restoration of normal diameter (19). It is unclear whether this mechanism is a local response, resulting from direct mechanical stimulation of sensory nerve endings, or whether it is part of a reflex arc with the trigeminal nerve constituting the afferent or efferent limb (Fig. 1).
Schematic illustration of the trigeminovascular reflex as shown by experiments in the cat (19, 50, 51). Irrespective which vasoconstrictor that was used the cortex arterioles dilated back to original diameter in the sensory innervated vessel within one minute but it was markedly prolonged in the trigeminal lesioned animal (CGRP was depleted from these vessels as shown both by immunocytochemistry and radioimmunoassay).
A protective mechanism such as the trigeminovascular reflex may have considerable pathological significance and is supported by clinical data:
Experimental data suggest depletion of CGRP from cerebral vessels in subarachnoid haemorrhage (SAH) (82);
The CGRP levels in cranial venous blood and in CSF correlate with the degree of cerebrovascular constriction in SAH that can be seen with transcranial Doppler (39, 83);
CGRP cannot be detected in cerebral blood vessels of patients that have died due to SAH (84), putatively because the peptide has been released in an unsuccessful attempt to maintain adequate levels of blood flow. In the same patients, cerebrovascular levels of other perivascular vasoactive peptides were close to the levels found in normal subjects.
Administration of CGRP to patients with symptomatic vasospasm can reverse the contraction if the blood pressure is carefully monitored (40) or in primates the administration of CGRP prevents cerebral vasospasm after a subsequent experimental SAH (85).
Thus, a vasomotor role in the trigemino-cerebrovascular system would not be to the exclusion of its involvement in nociception since intense pain often accompanies a SAH. The role of the trigemino-vascular system is almost the exact counterpart of the role of perivascular sympathetic fibres; the function of the vasoconstrictor system is not to reduce cerebral blood flow but rather to attenuate or prevent excessive vasodilatation, for example, extreme hypertension (86). The function of the vasodilatory trigeminal system is not to increase cerebral blood flow but rather to attenuate excessive cerebral vasoconstriction. The involvement of cerebrovascular autonomic fibres in situations where extremes of cerebral perfusion threatens the survival of neurons in the CNS does not require any reappraisal of the primacy of cerebral metabolism rather than neurogenic factors in determining tissue perfusion on a moment-to-moment basis.
CGRP receptors
CGRP is present in two forms α- and β-CGRP. Calcitonin and α-CGRP are transcribed from the same gene, while β-CGRP is formed from a separate CGRP gene (24, 25, 87, 88). Early pharmacological studies of CGRP receptors focused on the use of CGRP agonists and the CGRP fragment CGRP8-37 to discriminate between the CGRP receptor subtypes (27). The use of peptide antagonists to classify CGRP receptors has been criticized since experimental conditions may sometimes change the actions of these peptides and thereby limit their ability to reliably discriminate CGRP receptor subtypes (89).
Subsequent cloning efforts have resulted in the molecular identification of the CGRP receptor (Fig. 2) (90). Calcitonin receptor like receptor (CRLR) is a Gs-coupled seven-transmembrane domain G-protein-coupled receptor (GPCR) that shares 55% sequence identity with the calcitonin receptor. McLatchie et al. (91) demonstrated that functional CGRP and adrenomedullin receptors are both derived from CRLR and that the phenotype is determined by co-expression with a particular receptor activity modifying protein, RAMP. Co-expression of CRLR with RAMP1 results in CGRP receptor pharmacology while CRLR and RAMP2 or RAMP3 co-expression form adrenomedullin receptors. RAMPs are relatively small proteins(148–175 amino acids) containing a single membrane spanning domain, a large extracellular domain, and a short cytoplasmic domain (92). Three biological functions have been defined for RAMPs:
Demonstration of the RT-PCR product (339 base pair long) corresponding to mRNA encoding the human CGRP1 receptor in human cerebral (C), middle meningeal (M) and temporal arteries (T) (99).
They enable expression of CRLR on the cell surface and thereby determine the relative affinity of this receptor for CGRP and adrenomedullin (92);
CRLR internalization following CGRP stimulation has been shown to occur together with RAMP1, and both proteins are targeted to the protein degradation pathway (93). Although the receptors resulting from co-expression of CRLR with either RAMP1 or RAMP2/3 are functionally distinct, CGRP and adrenomedullin displayed some cross-reactivity for the opposite receptor (91);
RAMP proteins have, in addition, been shown to modulate the pharmacology of the calcitonin receptor, which in combination with RAMP1 or RAMP3, will bind amylin with high affinity (94, 95).
In addition to the RAMPs, the CGRP receptor may require another accessory protein for its function, the receptor component protein (RCP) (96). By using cell lines which express antisense RCP mRNA, it was demonstrated that the ability of CGRP to stimulate cAMP production was attenuated, although 125I-CGRP binding was unaffected (97). These observations suggest that RCP does not function as a molecular chaperone, but may instead be involved in coupling of the receptor to downstream signalling pathways. RAMP1 is required for glycosylation and proper transport of CRLR to the plasma membrane and RCP is necessary for coupling of the receptor to the cellular signal transduction machinery. Whether RCP is utilized by other GPCRs for G-protein signalling remains to be determined.
Pharmacological studies of cerebral and meningeal vessels from laboratory animals and man early revealed that CGRP-receptors dominate by inducing maximum dilatation while the responses to amylin and adrenomedullin are minor and mediated by the CGRP1 receptor (17, 22, 42, 98). The CGRP induced relaxation is endothelium independent and occurs in parallel with activation of adenylyl cyclase both in man (35, 41, 42, 68, 98) and in the cat (71). CGRP receptor mRNA has been demonstrated in human cranial arteries and in the human trigeminal ganglion (53, 99), thus demonstrating possible post- and pre-junctional CGRP receptors. Studies have, in addition demonstrated the expression of mRNAs encoding CRLR and all three RAMPs in the smooth muscle cell layer of human cranial arteries (69, 100). However, functionally it is the CGRP1 receptor profile that dominates.
Non-Peptide CGRP Receptor Antagonists
A breakthrough in the CGRP field came recently when researchers at Boehringer Ingelheim developed small molecules that were proven to be potent antagonists for the CGRP receptor; BIBN4096BS and compound 1 (101–107). The more potent of these, BIBN4096BS demonstrates extremely high affinity for human CGRP receptors expressed in SK-NM-C cells with an apparent pA2 value in the pM range. Interestingly, both antagonists are 2 or 3 log units more potent in human tissues as compared to that seen in experimental animals. The high affinity of BIBN4096BS and compound 1 for hCRLR/hRAMP1 was unusual and therefore analysed in detail. It was observed that this species selectivity was dictated strictly by hRAMP1 (108). The region between amino acids 66–112 was seen to be critical for determining the pharmacology. The exact molecular mechanisms by which RAMP1 modulates the antagonist binding apparently resides in a mutation of only one amino acid (108).
BIBN4096BS dose-dependently inhibits vasodilatation induced by electrical stimulation of the trigeminal ganglion in the marmoset (101). The results demonstrated that BIBN4096BS is a potent inhibitor of neurogenic vasodilatation, a putative model for antimigraine potential. In a separate report, BIBN4096BS and CGRP8-37 were shown to block the development of tolerance to morphine (109), further supporting the role of CGRP receptors in nociception. α-CGRP is, in human cerebral vessels, significantly more potent as a vasodilator than it is in peripheral, coronary, meningeal and temporal arteries (41, 68) and in addition BIBN4096BS acts as an excellent antagonist (102, 110, 111) (Fig. 3).
Relaxant effect of α-CGRP in human cerebral arteries (○, control) and the inhibition of this response by BIBN4096BS in increasing concentrations (shown as log M concentration); □ BIBN 10−10 M, ▪ BIBN 3 10−9 M, • BIBN 10−9 M. A clear parallel shift to the right indicate the competitive nature of the antagonist at the CGRP receptor (102).
The second small molecule, Compound 1, has been studied on CGRP induced responses in human cranial arteries (103). Compound 1 displaced 125I-CGRP from SK-N-MC cells and antagonized CGRP-induced cAMP production in the same cells with pA2 values of about 8. On human isolated cerebral arteries, Compound 1 caused a parallel shift to the right of the concentration-effect curve to CGRP without changing the maximum response, yielding a pA2 value of 10 n
A third small CGRP antagonistic molecule was recently presented, SB-(+)-273779, a selective nonpeptide antagonist of the CGRP1 receptor (112). SB-(+)-273779 inhibited CGRP binding to SK-N-MC, the human cloned CGRP1 receptor and the CGRP(3 n
Is there a need for a CGRP antagonist in migraine?
CGRP has long been regarded as a useful target for the development of novel antimigraine therapies. The excellent correlation between CGRP release and migraine headache has long pointed to the potential usefulness of a specific CGRP antagonist in the treatment of primary headache (36). It was observed that the triptans have the ability to inhibit the release of CGRP (30, 31, 38) via 5-HT1B/1D receptors on the sensory nerves (55–57,113) but these agents all suffer from cardiovascular side-effects of 3–5% in clinical trials to mild chest symptoms in up to 30–40% in clinical practice (114). The recent progress in the demonstration of the unique molecular biology and functional organization of the CGRP family of receptors has provided a detailed and unique understanding of the various elements of the receptor function. The development of small nonpeptide molecules with selectivety for human CGRP receptors has opened up the possibility to examine this in clinical studies.
At present CGRP is the only transmitter reliably found to be released in primary headaches. From our histochemical studies of human cranial arteries and trigeminal ganglia it has been shown that at least half of the cell bodies contain CGRP (53), but several other peptides and nitric oxide synthase are present in the trigeminal ganglion. In addition, the human CGRP-containing neurons express 5-HT1B/1D receptors (55), the activation of these reduce the CGRP release via a presynaptic inhibition via 5-HT1B/1D receptors which then can ameliorate the headache (31, 38). Ongoing clinical trials with BIBN4096BS in man have provided some answers; CGRP antagonism is effective in the treatment of acute migraine attacks and has no significant site effects (115). In a recent study the blocker was seen to have an efficacy similar to that of oral sumatriptan study; thus, BIBN4096BS had an effect of about 60% in doses up to 10 mg/patient given intravenously (116). Since there is at present no evidence that the novel CGRP receptor antagonists have direct contractile effects on human vasculature (101–103, 110, 111, 117) this may prove to be a significant advantage over the triptans given they have similar efficacy on the acute attacks.
Conclusion
Migraine is a common health problem that afflicts up to 15% of the adult population worldwide, it is present in children and the elderly but at lower frequency. It poses a considerable socio-economic burden to the individual and to society. The scientific work in the last decade has unravelled much of the pathophysiological background and suggests that it is a neurovascular disease. The developments of drugs of the triptan class has provided relief for the acute attacks at the cost of some side-effects, thus there still exists ample possibilities for improvements in the treatment. The discovery that the trigemino-vascular system is involved with release of CGRP, associated with the pain, during acute migraine and cluster headache attacks, provides the opportunity to directly block this receptor as a new target. Furthermore, CGRP administration in man may result in migraine attacks (118) and this response can be effectively aborted by administration of BIBN4096BS (76). The triptans have been found to act in part via presynaptic blockade of the release of CGRP. This has prompted the development of CGRP antagonists and in fact it has now been disclosed that one CGRP antagonist (BIBN4096BS) works to alleviate the acute migraine attack without significant side-effects and thus proves the concept. Further development of drugs against this receptor type will provide a significant therapeutic advance in the field of antimigraine drugs.
Footnotes
Acknowledgements
The studies of the authors’ reviewed have been supported by the Swedish Research Council (project no. 5958).