MIGRAINE PATHOPHYSIOLOGY


Abstract

We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during migraine is detrimental to the antimigraine action of the 5-HTIB/ID receptor agonists known as triptans. Because cutaneous allodynia is a manifestation of sensitization of central trigeminovascular neurons, we examined whether triptan treatment can intercept such sensitization before its initiation or after its establishment in our rat model for cutaneous allodynia induced by intracranial pain. Single-unit recordings were obtained from spinal trigeminal neurons that proved to receive convergent inputs from the dura and facial skin. The effects of sumatriptan (300 μg per kilogram i.v.) on central sensitization induced by topical application of inflammatory soup (IS) on the dura were determined when the drug was administered either 2 hours after IS (late intervention) or at the same time as IS (early intervention). Late sumatriptan intervention counteracted two aspects of central sensitization: dural receptive fields, which initially expanded by IS, shrunk back after treatment; neuronal response threshold to dural indentation, which initially decreased after IS, increased after sumatriptan. Conversely, late sumatriptan intervention did not reverse other aspects of central sensitization: spontaneous firing rate and neuronal response magnitude to skin brushing which initially increased after IS, remained elevated after sumatriptan; response threshold to heating of the skin, which initially dropped after IS, remained low after sumatriptan. Early sumatriptan intervention effectively blocked the development of all aspects of central sensitization expected to be induced 2 hours after IS application: dural receptive fields did not expand; neuronal response threshold to dural indentation and skin stimulation did not decrease; spontaneous firing rate did not increase. The early treatment results suggest that triptan action provides a powerful means of preventing the initiation of central sensitization triggered by chemical stimulation of meningeal nociceptors. The late treatment results suggest that triptan action is insufficient to counteract an already established central sensitization. Thus, triptan action appears to be exerted directly on peripheral rather than central trigeminovascular neurons.

For many migraine patients, triptan therapy provides complete pain relief in some attacks but not in others. Here, we tested whether the success of triptan therapy is hindered in the presence of cutaneous allodynia (pain resulting from a nonnoxious stimulus to normal skin), a phenomenon we previously described develops gradually during the course of the migraine attack in more than 70% of patients. We studied migraine patients repeatedly on three visits to the clinic: in the absence of migraine (baseline), within the first hour of one attack, or at 4 hours from the onset of another attack. Presence or absence of allodynia was determined based on differences between migraine and baseline pain thresholds to mechanical and thermal stimulation of periorbital skin. In 31 patients, we studied 34 migraine attacks that were associated with allodynia at the time of triptan treatment and 27 attacks that were not. Within 2 hours of triptan treatment, patients were rendered pain-free in 5 of 34 (15%) of allodynic attacks versus 25 of 27 (93%) of nonallodynic attacks. Treating migraine attacks 1 hour (early) or 4 hours (late) after the onset of pain was equally ineffective in inducing a pain-free state in the presence of allodynia, and equally effective in the absence of allodynia. For patients susceptible to allodynia during the attack, triptan therapy was by far more likely to provide complete pain relief if administered before rather than after the establishment of cutaneous allodynia. Patients who never developed allodynia were highly likely to be rendered pain-free by triptan therapy anytime after the onset of pain. We conclude that the probability of consistent pain-free outcome increases drastically if triptan therapy is vigilantly timed to precede any signs of cutaneous allodynia.

Triptans are 5-HT1B/1D receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5-HT1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization.

Comments: We asked Dr. Richard Hargreaves of Merck, who synthesized rizatriptan, to do a guest set of comments on these three studies by Dr. Burstein:

The recent trilogy of papers both preclinical and clinical by the Burstein group, back to back in Annals of Neurology1,2 and most recently in PNAS3 extend support for a key central action of the 5-HT1B/1D agonist triptan antimigraine agents and suggest that observation of a migraine “phenotype” may be useful to ensure the maximal acute antimigraine efficacy of this class of therapeutics.

While reading these papers, it is essential to have a clear conceptual view of the anatomy and neuropharmacology of the trigeminovascular system. Trigeminal neurons have their cell bodies in the trigeminal ganglion, and this is located in the periphery. These cells are classified as pseudo-unipolar primary sensory neurons, which means that—contrary to what the nomenclature may infer—they have two key axonal projections. One of these extends within the periphery to the meninges and terminates in a dense plexus of trigeminal sensory fibers surrounding the meningeal blood vessels. Immunohistochemical studies have shown that these fibers contain the sensory neuropeptides substance P and CGRP consistent with the characteristics of C and Aδ fibers. The other pole of the primary sensory trigeminal neurons projects centrally behind the blood brain barrier to the trigeminal nuclei in the brain stem where it synapses onto the secondary sensory neurons within the central nervous system. The trigeminal neurons thus mediate pain signal transmission from the periphery into the central nervous system. Many of the second order sensory neurons in the brain stem serve a dual role in that they relay information about noxious painful stimuli as well as nonnociceptive sensory information. In this respect they are sometimes called convergent sensory neurons. Thus, it has been proposed that during a migraine attack the intense sensory bombardment of these neurons causes them to become sensitized to all stimuli such that previously innocuous events become exaggerated. This is the physiological basis of the allodynia that has been documented in detail by the Burstein group in migraine patients during an attack.

The elegant experimental studies of Burstein et al now provide further evidence that a key action of the triptans is through inhibition of pain transmission at the central synapse between the primary trigeminal neurons and the second order sensory neurons in the brain stem. This prejunctional site of action, centrally on the terminals of incoming trigeminal fibers, has been proposed previously for the triptans by the groundbreaking studies from Goadsby4 and others over a number of years. It is well known that prejunctional inhibition of transmitter release mediated by agonist drugs such as the triptans is dependent both on the efficacy of the drug molecule and the frequency of firing of the nerve fibers. Thus, it is not surprising that when attacks begin before pain intensity reaches its greatest intensity that it is easier to shut the nerve fibers down. Indeed, this is the basis for the treat early or treat mild school of thinking to obtain the highest response rates with triptan use. It also follows that the earlier you treat, the less likely it is for allodynia to develop in the second order neurons within the brainstem, as these neurons will not have become maximally sensitized. These recent observations, both preclinically and clinically, place this pharmacology in a context of migraine phenotypes that evolve during an attack or characterize different attacks or patients.

In their discussions, Burstein et al comment that previous studies have focused on the effects of triptans on nonsensitized trigeminal neurons and so question their relevance to migraine. However, it should be noted that these earlier studies aimed not to model migraine in rodents but to define pharmacologically a potential central site of action for the triptan drugs, and so in essence the earlier studies concur with these recent findings. While the current studies focus on central trigeminal inhibition as the key site in the mechanism of action of the triptans, it should be remembered that there is also good clinical evidence for triptan: (1) vasoconstriction of cerebral meningeal blood vessels and that this rather than central actions of poorly brain penetrant drugs such as the triptans may be the best explanation for the fast action of subcutaneous sumatriptan and (2) inhibition of neuropeptide release during migraine attacks through an inhibitory action at the peripheral perivascular terminals of the trigeminal sensory nerves, as shown by the reduction in release of the potent vasodilator calcitonin gene related peptide (CGRP) by the triptans reported by several groups including Edvinsson and Goadsby.5 The importance of CGRP release in the migraine cascade is now supported by the recent demonstration6 that CGRP receptor antagonists are effective acutely against migraine (see Olesen abstract below). Indeed, it can be argued that if the neurons in the trigeminal ganglion produce receptors they should export them throughout their processes to both central and peripheral terminals. Thus, if the triptans inhibit transmitter release centrally through an action on the trigeminal nerve terminals, they should also be capable of doing the same in the periphery, and the blockade of CGRP release by the triptans is consistent with this view. The studies of Cumberbatch et al7 linked these phenomena in a pharmacological proof of concept study by driving meningeal vasodilatation using low doses of CGRP. The data showed that even after short periods of 6 minutes this was sufficient to begin sensitizing convergent sensory neurons to mild sensory stimuli such as vibrissal stimulation, and that this could be inhibited by the triptan agents. Although criticized by Burstein et al, these early studies were the forerunner of the current migraine allodynia model and clearly suggested that triptans could act to prevent changes in nonnociceptive sensory processing by the second order neurons. The current studies extend these observations using more profound sensitizing conditions that produce receptive field expansion and changes to thermal and mechanical stimuli. It is, however, worth remembering that one of the most potent classes of inhibitors of these phenomena in preclinical models are substance P(NK1) receptor antagonists, and these were found to have no efficacy in the acute treatment of migraine, indicating that the laboratory model, while a useful tool, does not mimic all pharmacological aspects of the clinical condition. Indeed a clear therapeutic role for blockers of the key pain transmitter glutamate, that are also highly active against sensitization in these models, has yet to be defined in migraine therapy.

In conclusion, there is still plausible clinical and experimental evidence for three key sites of triptan action: (1) 5-HT1B on the meningeal blood vessels producing constriction, (2) 5-HT1D on the peripheral terminals of the trigeminal nerves preventing release of vasodilator peptides such as CGRP, and (3) 5-HT1D on the central terminals of the trigeminal fibers preventing pain signal transmission to the second order sensory neurons in the brain stem. One final mystery is the potential involvement of 5-HT1B receptors that are widespread on cell bodies throughout pain pathways in the CNS and will undoubtedly become activated when the triptans penetrate the brain. These deserve more attention and may have a role in modulation of ascending or descending pain control pathways; unraveling their involvement in the efficacy and typical central side effect profiles of the triptans would be of great interest.

Finally, what next? It is now time to consider a step-wise investigation of the central mechanisms that could be involved in migraine allodynia and the actions of antimigraine drugs noninvasively in human subjects using an objective quantitative measure such as fMRI. Studies of the somatotopic activation of brain-stem trigeminal nuclei and perhaps even the trigeminal ganglion8,9 could parallel observations of migraine phenotype and provide another potential link to preclinical models. This would be truly breakthrough primary headache research.

Richard Hargreaves

REFERENCES

1. Burstein R, Collins B, Jakubowski M. Defeating migraine pain with the Triptans: A race against the development of cutaneous allodynia. Ann Neurol. 2004;55: 19-26.

2. Burstein R, Jakubowski M. Analgesic Triptan action in an animal model of cranial pain: A race against the development of sensitization. Ann Neurol. 2004;55: 27-36.

3. Levy D, Jakubowski M, Burstein R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the anti-migraine action of 5-HT1B/1D agonists. Proc Nat Acad Sci. 2004;101: 4274-4279.

4. Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by intravenous administration of the serotonin 5-(5-HT) 1D receptor agonist zolmitriptan (311C90): are brain stem sites a therapeutic target in migraine Pain. 1996;67: 355-359.

5. Edvinsson L, Goadsby PJ. Neuropeptides in headache. Eur J Neurol. 1998;5: 329-341.

6. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene related peptide antagonist BIBN 4096BS for the acute treatment of migraine. New Engl J Med. 2004;350: 1104-1110.

7. Cumberbatch MJ, Williamson DJ, Mason GS, Hill RG, Hargreaves RJ. Dural vasodilatation causes sensitization of rat caudal trigeminal neurons in vivo that is blocked by a 5-HT1B/1D agonist. Brit J Pharmacol. 1999;126: 1478-1486.

8. DaSilva AF, Becerra L, Makris N, Strassman AM, Gonzalez RG, Geatrakis N, Borsook D. Somatotopic activation in the human trigeminal pain pathway. J Neurosci. 2002;22: 8183-8192.

9. Borsook D, DaSilva AF, Ploghaus A, Becerra L. Specific and somatotopic fMRI activation in the trigeminal ganglion by brush and noxious heat. J Neurosci. 2003; 23: 7897-7903.

I guess that these studies vindicate the Winner et al studies on early intervention sponsored by GlaxoSmithKline (GSK), which suggested that early treatment with triptans results in greater overall efficacy than previous studies which had the patients treated when pain crossed the moderate/severe category. The latter strategy, the one used in most triptan regulatory trials, would encourage the development of cutaneous allodynia and ensuing treatment resistance. David S. Millson

The three studies by Dr. Burstein et al have significant clinical implications, and suggest that the development of central sensitization, and allodynia, as a marker for it, are connected with triptan failure, as measured by pain-free response. If we can measure the presence or absence of allodynia in migraine patients, or patients can accurately recall whether they get it, we can decide which patients need very early intervention with triptans versus which can be more leisurely in administering the drugs. The fact that there are two groups, those that get allodynia and those that do not, explains why there is a demonstrable pain-free rate in the population of patients treated when pain is moderate to severe. It also suggests that by treating early in population studies (e.g., Winner P, Mannix LK, Putnam DG, McNeal S, Kwong J, O'Quinn S, Richardson MS. Pain-free results with sumatriptan taken at the first sign of migraine pain: two randomized, double-blind, placebo-controlled studies. Mayo Clin Proc. 2003;78:1214-1222; Klapper J, Rosjo O, Charlesworth B, Jergensen AP, Soisson T. Treatment of mild migraine with oral zolmitriptan 2.5 provides high pain-free response rates in patients with significant migraine-related disability. Neurology. 2002;58:A416h (abs); Cady R, Keywood C. Early intervention with frovatriptan: a review of efficacy. Cephalalgia 2002;22:602-603 (abs), etc) pain-free results are so high—both groups are captured. Stewart J. Tepper

5-Hydroxytryptamine (1A) (5-HT1A) receptor activation reduces body temperature partially by dilating the thermoregulatory cutaneous vascular bed, thereby increasing heat transfer to the environment. Constriction of this vascular bed, with consequent reduction of heat transfer to the environment, contributes to fever associated with the acute inflammatory response. Thus activation of 5-HT1A receptors might inhibit thermoregulatory cutaneous vasoconstriction and reduce the fever associated with the acute inflammatory response. The present study tested this hypothesis in conscious unrestrained rabbits. The acute inflammatory reaction was induced with i.v. lipopolysaccharide (LPS, .5 μg per kilogram). Body temperature was measured with an i.p. telemetric probe, and ear pinna blood flow was measured with a chronically implanted Doppler ultrasonic probe. 5-HT1A receptors were activated with i.v. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). LPS increased body temperature by +1.7 ± .2°C during the first hour after administration. The ear pinna Doppler blood flow signal fell from 69 ± 11 to 5 ± 1 cm per second within 15 minutes (n = 7, P < .01) and remained at a low level for approximately 1 hour after LPS. When administered 45 minutes after LPS, 8-OH-DPAT (.1 mg per kilogram i.v.) reversed this fall, increasing the Doppler signal from 6 ± 1 to 55 ± 7 cm per second (P < .01, n = 6), and reduced the rise in body temperature. Treatment with 8-OH-DPAT (.1 mg per kilogram i.v.) 5 minutes before and 30 minutes after LPS entirely prevented the LPS-induced fall in ear pinna blood flow, and reduced the rise in body temperature from 1.7 ± .2°C to .7 ± .2 (n = 7, P < .01). Treatment with WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride) (.1 mg per kilogram i.v.) prevented and reversed the effects of 8-OH-DPAT. Thus activation of 5-HT1A receptors reduces thermoregulatory cutaneous vasoconstriction and fever occurring as part of the acute inflammatory response. Our findings elucidate the neurotransmitter mechanisms underlying expression of an important component of the febrile response, and suggest that drugs with 5-HT1A agonist properties might be therapeutically useful when it is clinically important to reduce this response.

Comments: Clinicians have long noted paradoxical effects from ergotamine and DHE (dihydioergotamine) when a migraine appears to worsen before improving after treatment. Dr. Neil Raskin used to say that this “overshoot,” which is also sometimes manifested with nausea as well as increased pain, could be corrected by lowering the ergot dose. Dr. Raskin recommended establishing the maximal subnauseating dose of DHE for treatment. Could the worsening be due to the vasodilating effect of ergot 5-HT1A agonism at the higher doses?

Triptan effects on 5-HT1A receptors are just being elucidated, and may also account for the occasional worsening clinicians observe after treating. Please see the abstract below under Migraine Treatment by Boers et al. Stewart J. Tepper

The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 minutes before and after the nitroglycerin application, and 60 and 120 minutes after the beginning of the migraine attack (mean 344 and 404 minutes; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly (P < .01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity (P < .001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly (P < .01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.

Comments: This raises important questions about peptides or kinins released during migraine attacks. Are they implicated in causation or are they simply bystanders? The recently published lack of efficacy for Neurokinin antagonists (NK1) in the treatment of migraine suggest a bystander effect for substance P, whereas the recent efficacy reported by Dr. Jes Olesen et al for the CGRP antagonist BIBN 4096 BS (see below) as an effective treatment for acute migraine suggest a causative pathophysiological role for CGRP. David S. Millson and Stewart J. Tepper

Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-α (PKGI-α), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-α attenuates signaling by the thrombin receptor protease-activated receptor-1 (PAR-1) through direct activation of regulator of G-protein signaling-2 (RGS-2). NO donors and cGMP cause cGMP-mediated inhibition of PAR-1 and membrane localization of RGS-2. PKGI-α binds directly to phosphorylates RGS-2, which significantly increases GTPase activity of G(q), terminating PAR-1 signaling. Disruption of the RGS-2-PKGI-α interaction reverses inhibition of PAR-1 signaling by nitrovasodilators and cGMP. RGS-2/mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-α binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. Our study shows that RGS-2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.

Comments: Here is a complex cascade that mediates vasodilation via nitric oxide (NO). If Professor Jes Olesen and others are right (Lassen LH, Ashina M, Christiansen I. Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia. 1998;18:27-32), this NO-vasodilation axis is the pathway to migraine vascular change. Thus, these proteins are also targets for migraine medications. Stewart J. Tepper

Ancillary