F. Michael Cutrer

Mechanisms of migraine aura revealed by functional MRI in human visual cortex

Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 ± 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.

2003 Wolff Award: Possible parasympathetic contributions to peripheral and central sensitization during migraine.

Background.—Neurologic signs of increased parasympathetic outflow to the head often accompany migraine attacks. Because increased parasympathetic outflow to the cranial cavity induces vasodilation of cerebral and meningeal blood vessels, it can enhance plasma protein extravasation and the release of proinflammatory mediators that activate perivascular nociceptors. We recently showed that activation of intracranial perivascular nociceptors induces peripheral and central sensitization along the trigeminovascular pathway and proposed that these sensitizations mediate the intracranial hypersensitivity and the cutaneous allodynia of migraine.

The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis

&NA; The effect of the N‐methyl‐d‐aspartate (NMDA) receptor antagonist (5R,10S)‐(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine hydrogen maleate (MK‐801) was examined on c‐fos‐like immunoreactivity (c‐fos‐LI) in urethane‐anesthetized Sprague‐Dawley rats using a polyclonal antibody. C‐fos, an indicator of neuronal activation, was assessed within the trigeminal nucleus caudalis (TNC), area postrema, lateral reticular and solitary tract nuclei 2 h after intracisternal injection of capsaicin. C‐fos‐positive cells were counted at three representative levels corresponding to obex, −2.05 mm and −6.45 mm in 18 tissue sections (50 &mgr;m). A weighted average was obtained reflecting total brainstem expression within lamina I, II of TNC using a recently validated method. Capsaicin (0.1, 1, 5, 10 and 15 nmol) caused a dose‐dependent labeling of cells in lamina I, II at obex similar to that previously reported after intracisternal blood or carrageenin administration in rats and guinea pigs. MK‐801 (0.3, 1 and 3 mg/kg) administered i.p. 30 min before capsaicin (5 nmol in 100 &mgr;l artificial CSF) reduced significantly and dose‐dependently (12%, 36% and 47%, respectively) the c‐fos‐LI cells in TNC at each level from rostral to caudal but not in solitary tract, area postrema and lateral reticular nuclei, and for unexplained reasons, increased c‐fos‐LI within the inferior olive. These results suggest that NMDA receptors provide a potential therapeutic target for cephalic pain (e.g. migraine) due to trigeminovascular activation from meningeal afferents.

The Actions of Valproate and Neurosteroids in a Model of Trigeminal Pain

Gamma‐aminobutyric acid (GABA) receptors are ubiquitous inhibitory receptors in the central and peripheral nervous systems. Valproic acid (2‐propylpentanoic acid), which enhances GABA synthesis and blocks degradation, is useful in migraine treatment and may act through activation of GABA receptors to modulate trigeminal nociceptive neurons innervating the meninges. To investigate this possibility, we tested the effect of valproate and allopregnanolone, a metabolite of progesterone, which binds and modulates the GABA receptor in an animal model of cephalic pain.

Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin

1 Valproic acid, useful in the treatment of migraine, is an inhibitor of γ‐aminobutyric acid (GABA) aminotransferase and activator of glutamic add decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2‐propylpentanoic acid) were examined on the number of cells expressing c‐fos‐like immunoreactivity (c‐fos‐LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, II0; TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 μ ml−1, in urethane‐anaesthetized Hartley guinea‐pigs. Positive cells were counted in eighteen sections (50 μm) at three representative levels (rostral, middle and caudal) within lamina I, II0 of the TNC in 90 animals. 2 Numerous cells were labelled after capsaicin instillation (244 ± 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 ± 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. 3 Valproate (≥ 10 mg kg−1, i.p.) reduced labelled cells by 52% (P<0.05) in lamina I, II0 but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4 Pretreatment with bicuculline (30 μg kg−1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg−1) a GABAB antagonist, reversed the effect of valproate and increased c‐fos positive cells within lamina I, II0. Somewhat paradoxically, bicuculline by itself (30 μg kg−1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c‐fos expression. 5 We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c‐fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches.

Peripheral GABAA receptor‐mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation

1 The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA‐agonist muscimol on dural plasma protein ([125I]‐bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg−1, i.v.) in anaesthetized Sprague‐Dawley rats. 2 Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (≤10 mg kg−1, i.p.) dose‐dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6±1.4 mg kg−1, i.p., and 58 + 18 μg kg−1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2±1.4 mg kg−1, i.p. and 385±190 μg kg−1, i.p. for valproate or muscimol, respectively). 3 Valproate (6.6 mg kg−1, i.p.) or muscimol (58 μ kg−1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4 The GABAA‐antagonist bicuculline (0.01 mg kg−1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB‐receptor antagonist, phaclofen (0.01‐1 mg kg−1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5 Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline‐reversible mechanism. This suggests that GABAA‐receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats. 6 We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA‐mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.

Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis.

We examined the effects of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate receptor antagonists 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) and 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzol[f]quinoxaline‐7‐sulphonamide (NBQX), the kainate receptor antagonists γ‐(R‐)‐glutamylaminomethanesulphonic acid (GAMS) and 6,7,8,9‐tetrahydro‐5‐nitro‐1H‐benz[g]indole‐2,3‐dione‐3‐oxime (NS‐102), and the group III metabotropic glutamate receptor (mGluR) agonist 2‐amino‐4‐phosphono‐S‐butanoic acid (L‐AP4) on c‐fos‐like immunoreactivity (c‐fos LI) in trigeminal caudalis (Sp5C), lateral reticular (LRt), medullary reticular (Md) and solitary tract (Sol) nuclei, after intracisternal injection of capsaicin in urethane anaesthetized Sprague‐Dawley rats. Few c‐fos labelled cells were observed within Sp5C in capsaicin‐vehicle treated animals. The number of positive c‐fos cells increased by 17 fold after intracisternal capsaicin (5 nmol) administration. Pretreatment with CNQX (0.02, 0.1, 0.6, 3 and 15 mg kg−1) or NBQX (0.01, 0.1 and 1 mg kg−1), administered intraperitoneally 15 min before capsaicin, significantly reduced labelled cells within Sp5C by a maximum of 45 and 34%, respectively. The number of c‐fos LI cells within LRt, Md and Sol was not affected. Pretreatment with  L‐AP4 (1, 3 and 10 mg kg−1) decreased the number of Sp5C c‐fos LI cells by a maximum of 30%, whereas GAMS (1 and 10 mg kg−1) and NS‐102 (1 and 5 mg kg−1) did not show any significant effect. These results suggest that blockade of AMPA receptors, but not kainate receptors, or the activation of group III mGluRs, decrease the response of Sp5C neurons to trigeminovascular activation. Thus, in addition to NMDA receptors, mGluRs and AMPA receptors may modulate cephalic pain and may provide a potential therapeutic target for antimigraine drugs.

Pathophysiology of Migraine

Our understanding of migraine pathophysiology is a work in progress. As more is learned about migraine, it seems that the probability of identifying a single unifying explanation for this common disorder becomes less and less. Although the neuroanatomy and elements of pain physiology underlying migraine attacks are probably shared pathophysiologic elements, the emerging complexity of migraine genetics suggests that the acute attack may be the final common expression of more than one type of initiating abnormality. After a brief summary of the neuroanatomic structures involved in the generation of migraine attacks and the traditional theories of migraine, the author focuses on the current understanding of migraine genetics and reviews recent data from the neuroimaging and the neurophysiology of migraine.

Effects of PNU-109,291, a selective 5-HT1D receptor agonist, on electrically induced dural plasma extravasation and capsaicin-evoked c-fos immunoreactivity within trigeminal nucleus caudalis.

We studied the effects of PNU-109291 [(S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isoc hroman-6-carboxamide], a receptor agonist showing 5000-fold selectivity for primate 5-HT1D versus 5-HT1B receptors (Ennis et al., J. Med. Chem. 41, 2180-2183), on dural neurogenic inflammation and on c-fos like immunoreactivity within trigeminal nucleus caudalis evoked by electrical and chemical activation of trigeminal afferents, respectively. Subcutaneous injection of PNU-109291 in male guinea pigs dose-dependently reduced dural extravasation of [125I]-labeled bovine serum albumin evoked by trigeminal ganglion stimulation with an IC50 of 4.2 nmol kg(-1). A dose of 73.3 nmol kg(-1) blocked the response completely. The selective 5-HT1B/1D receptor antagonist GR-127935 (> or = 2 micromol kg(-1) i.v.) prevented this effect. In addition, the number of c-fos immunoreactive cells within guinea pig trigeminal nucleus caudalis induced by chemical meningeal stimulation (intracisternally administered capsaicin) was reduced by more than 50% with PNU-109291 (> or = 122.2 nmol kg(-1) administered s.c. 45 min before and 15 min after capsaicin). These data indicate that the 5-HT1D receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models. Since 5-HT1D receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle, the 5-HT1D receptor subtype may become a useful therapeutic target for migraine and related headaches.

Imaging findings of migraine.

Increasingly sophisticated neuroimaging techniques have allowed researchers to begin to define functional and anatomical characteristics of migraine. This paper reviews current knowledge and techniques employed. Assessing present‐day knowledge limitations it concludes that with parallel advances in the technology of imaging and the pathophysiologic understanding of migraine, a reliable biomarker may be discovered in the future.