Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors.

Migraine is a common and disabling neurologic disorder, with important psychiatric comorbidities. Its pathophysiology involves activation of neurons in the trigeminocervical complex (TCC). Kainate receptors carrying the glutamate receptor subunit 5 (GluK1) are present in key brain areas involved in migraine pathophysiology. To study the influence of kainate receptors on trigeminovascular neurotransmission, we determined the presence of GluK1 receptors within the trigeminal ganglion and TCC with immunohistochemistry. We performed in vivo electrophysiologic recordings from TCC neurons and investigated whether local or systemic application of GluK1 receptor antagonists modulated trigeminovascular transmission. Microiontophoretic application of a selective GluK1 receptor antagonist, but not of a nonspecific ionotropic glutamate receptor antagonist, markedly attenuated cell firing in a subpopulation of neurons activated in response to dural stimulation, consistent with selective inhibition of postsynaptic GluK1 receptor-evoked firing seen in all recorded neurons. In contrast, trigeminovascular activation was significantly facilitated in a different neuronal population. The clinically active kainate receptor antagonist LY466195 attenuated trigeminovascular activation in all neurons. In addition, LY466195 demonstrated an N-methyl-d-aspartate receptor-mediated effect. This study demonstrates a differential role of GluK1 receptors in the TCC, antagonism of which can inhibit trigeminovascular activation through postsynaptic mechanisms. Furthermore, the data suggest a novel, possibly presynaptic, modulatory role of trigeminocervical kainate receptors in vivo. Differential activation of kainate receptors suggests unique roles for this receptor in pro- and antinociceptive mechanisms in migraine pathophysiology.

Differential trigeminovascular nociceptive responses in the thalamus in the familial hemiplegic migraine 1 knock-in mouse: a Fos protein study.

Familial hemiplegic migraine type 1 (FHM-1) is a monogenic subtype of migraine with aura caused by missense mutations in the CACNA1A gene, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels. Transgenic knock-in mice expressing the CACNA1A R192Q mutation that causes FHM-1 in patients show a greater susceptibility to cortical spreading depression, the likely underlying mechanism of typical human migraine aura. The aim of this study was to compare neuronal activation within the trigeminal pain pathways in response to nociceptive trigeminovascular stimulation in wild-type and R192Q knock-in mice. After sham surgery or electrical stimulation of the superior sagittal sinus for 2h, or stimulation preceded by treatment with naratriptan, mice underwent intracardiac perfusion, and the brain, including the brainstem, was removed. Fos expression was measured in the trigeminocervical complex (TCC) and the lateral (ventroposteromedial, ventrolateral), medial (parafascicular, centromedian) and posterior thalamic nuclei. In the TCC of wild-type animals, the number of Fos-positive cells increased significantly following dural stimulation compared to the sham control group (P<0.001) and decreased after naratriptan treatment (P<0.05). In R192Q knock-in mice, there was no significant difference between the stimulated and sham (P=0.10) or naratriptan pre-treated groups (P=0.15). The number of Fos-positive cells in the R192Q stimulated group was significantly lower compared to the wild-type stimulated mice (P<0.05). In the thalamus, R192Q mice tended to be more sensitive to stimulation compared to the sham control in the medial and posterior nuclei, and between the two strains of stimulated animals there was a significant difference in the centromedian (P<0.005), and posterior nuclei (P<0.05). The present study suggests that the FHM-1 mutation affects more rostral brain structures in this experimental paradigm, which offers a novel perspective on possible differential effects of mutations causing migraine in terms of phenotype-genotype correlations.

Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and "triptan" receptors: implications in migraine.

Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine. Endocannabinoids, as well as being physiologically analgesic, are known to inhibit dural trigeminovascular nociceptive responses. They are also involved in the descending modulation of cutaneous-evoked C-fiber spinal nociceptive responses from the brainstem. The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and/or cutaneous facial trigeminovascular nociceptive responses, from the brainstem ventrolateral periaqueductal gray (vlPAG). CB1 receptor activation in the vlPAG attenuated dural-evoked Aδ-fiber neurons (maximally by 19%) and basal spontaneous activity (maximally by 33%) in the rat trigeminocervical complex, but there was no effect on cutaneous facial receptive field responses. This inhibitory vlPAG-mediated modulation was inhibited by specific CB1 receptor antagonism, given via the vlPAG, and with a 5-HT1B/1D receptor antagonist, given either locally in the vlPAG or systemically. These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ-fiber dural-nociceptive responses, which differs from the way the brainstem modulates spinal nociceptive transmission. Furthermore, our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information, suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG.

A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization.

Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.

Inhibition of trigeminovascular dural nociceptive afferents by Ca(2+)-activated K(+) (MaxiK/BK(Ca)) channel opening.

Migraine is an episodic brain disorder with a significant morbidity. It is thought that activation of trigeminal afferents innervating the dura mater and large cerebral blood vessels is involved in the expression of the disorder. The selective large conductance calcium-activated potassium channels, the BK(Ca) or MaxiK channels, are intrinsic membrane proteins that are widely distributed in the brain. These channels are thought to be involved in controlling neuronal excitability and perhaps transmitter release, possibly in the trigeminocervical complex. We sought to investigate the role of MaxiK/BK(Ca) channels opening in several models of trigeminovascular nociception using NS1619, a benzimidazolone analogue. Intravenously administered NS1619 (10 mg kg(-1)) was able to inhibit neurogenic dural vasodilation (F(4,20)=19.23, P<0.05, n=6). NS1619 (intravenous) was not able to inhibit Aδ-fiber (F(3.01,18.06)=0.79, P=0.52) or C-fiber (F(3.14,18.84)=0.76, P=0.54) afferents in the trigeminal nucleus caudalis and C(1) region of the dorsal horn after dural electrical stimulation, but it was able to inhibit Aδ-fiber afferents after iontophoretic application of NS1619 (t(5)=3.23, P<0.05, n=6) after 5 min. Iontophoresed NS1619 was also able to inhibit l-glutamate induced firing in the trigeminocervical complex, in a dose-dependent manner (F(3,54)=3.06, P<0.05). The data taken together indicate that the MaxiK/BK(Ca) channel may represent a novel therapeutic target in migraine.

Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents.

OBJECTIVE: To understand the mechanism of action of oxygen treatment in cluster headache. BACKGROUND: Trigeminal autonomic cephalalgias, including cluster headache, are characterized by unilateral head pain in association with ipsilateral cranial autonomic features. They are believed to involve activation of the trigeminovascular system and the parasympathetic outflow to the cranial vasculature from the superior salivatory nucleus (SuS) projections through the sphenopalatine ganglion, via the greater petrosal nerve of the VIIth (facial) cranial nerve. Cluster headache is remarkably responsive to treatment with oxygen, and yet our understanding of its mode of action is unknown. METHODS: Combining models of trigeminovascular nociception and a novel approach that activates the trigeminal-autonomic reflex, using SuS/facial nerve stimulation, we explored the effect of oxygen on trigeminal nerve activation as well as on autonomic responses through blood flow observations of the lacrimal duct/sac. RESULTS: Meningeal vasodilation and neuronal firing in the trigeminocervical complex (TCC), in response to dural electrical stimulation, was unaffected by treatment with 100% oxygen. Stimulation of the SuS via the facial nerve caused only marginal changes in dural blood vessel diameter, but did result in evoked firing in the TCC. Two populations of neurons were characterized, those responsive to 100% oxygen treatment, with a maximal inhibition of 33%, 20 minutes after the start of oxygen treatment (t(15) = 4.4, P < .0001). A second population of neurons were not inhibited by oxygen and tended to have shorter latency. Oxygen also inhibited evoked blood flow changes in the lacrimal sac/duct caused by SuS stimulation. CONCLUSIONS: The data provide the first systematic, experimental evidence for a mechanism of action of oxygen in cluster headache. The data show oxygen has no direct effect on trigeminal afferents, acting specifically on the parasympathetic/facial nerve projections to the cranial vasculature to inhibit both evoked trigeminovascular activation and activation of the autonomic pathway during cluster headache attacks. Moreover, the studies begin to characterize a novel laboratory model for the most painful primary headache syndrome known--cluster headache.

Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat.

Functional imaging studies and clinical evidence suggest that structures in the brainstem contribute to migraine pathophysiology with a strong association between the brainstem areas, such as periaqueductal gray (PAG), and the headache phase of migraine. Stimulation of the superior sagittal sinus (SSS) in humans evokes head pain. Second-order neurons in the trigeminal nucleus that are activated by SSS stimulation can be inhibited by PAG stimulation. The present study was undertaken to identify pontine and medullary structures that respond to noxious stimulation of the superior sagittal sinus or to ventrolateral PAG stimulation. The distribution of neurons expressing the protein product (fos) of the c-fos immediate early gene were examined in the rostral medulla and caudal pons of the cat after (i) sham, (ii) stimulation of the superior sagittal sinus, (iii) stimulation of the superior sagittal sinus with PAG stimulation, or (iv) stimulation of the PAG alone. The structures examined for fos were the trigeminal nucleus, infratrigeminal nucleus, reticular nuclei, nucleus raphe magnus, pontine blink premotor area, and superior salivatory nucleus. Compared with all other interventions, fos expression was significantly greater in the trigeminal nucleus and superior salivatory nucleus after SSS stimulation. After PAG with SSS stimulation, on the side ipsilateral to the site of PAG stimulation, fos was significantly greater in the nucleus raphe magnus. These structures are likely to be involved in the neurobiology of migraine.

Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study.

Clinical observations, particularly of the premonitory phase of migraine, suggest the involvement of the hypothalamus in the earliest phases of an attack. Stimulation of the superior sagittal sinus (SSS) in humans produces head pain and permits study of the activated trigeminovascular system in experimental settings. The distribution of neurons expressing the protein product (Fos) of the c-fos immediate early gene was examined in the hypothalamus of anaesthetised (alpha-chloralose) cats. Animals were studied after either 2-h stimulation of the SSS or sham stimulation. Fos protein was detected using immunohistochemistry, and positive neurons were plotted onto standardised templates and counted by a blinded observer. In response to electrical stimulation of the superior sagittal sinus, we found significant activation of the supra-optic nucleus (SON) rising from 3 (0-13) (median, 95% confidence interval) to 53 (31-78; P = 0.005) fos-positive cells. In the posterior hypothalamic area (Hp), fos-positive cells rose from 4 (0-14) to 35 (17-45; P = 0.015) Taken together with other physiological studies, the data are consistent with a role for hypothalamic structures in the modulation of trigeminovascular nociceptive afferent information, and thus for a role in headache.