XiChun Zhang

Activation of Meningeal Nociceptors by Cortical Spreading Depression: Implications for Migraine with Aura

Attacks of migraine with aura represent a phenomenon in which abnormal neuronal activity in the cortex produces sensory disturbances (aura) some 20–40 min before the onset of headache. The purpose of this study was to determine whether cortical spreading depression (CSD)—an event believed to underlie visual aura—can give rise to activation of nociceptors that innervate the meninges—an event believed to set off migraine headache. CSD was induced in anesthetized male rats by stimulation of the visual cortex with electrical pulses, pin prick, or KCl; single-unit activity of meningeal nociceptors was monitored in vivo in the rat before and after CSD. Regardless of the method of cortical stimulation, induction of CSD was recorded in 64 trials. In 31 of those trials, CSD induced a twofold increase in meningeal nociceptor firing rate that persisted for 37.0 ± 4.6 min in trials in which activity returned to baseline, or >68 min in trials in which activity remained heightened at the time recording was interrupted. In two-thirds of the trials, onset of long-lasting neuronal activation began ∼14 min after the wave of CSD. The findings demonstrates for the first time that induction of CSD by focal stimulation of the rat visual cortex can lead to long-lasting activation of nociceptors that innervate the meninges. We suggest that migraine with aura is initiated by waves of CSD that lead up to delayed activation of the trigeminovascular pathway.

Activation of central trigeminovascular neurons by cortical spreading depression

Cortical spreading depression (CSD) has long been implicated in migraine attacks that begin with visual aura. Having shown that a wave of CSD can trigger long‐lasting activation of meningeal nociceptors—the first‐order neurons of the trigeminovascular pathway thought to underlie migraine headache—we now report that CSD can activate central trigeminovascular neurons in the spinal trigeminal nucleus (C1–2).

Sensitization and Activation of Intracranial Meningeal Nociceptors by Mast Cell Mediators

Intracranial headaches such as migraine are thought to result from activation of sensory trigeminal pain neurons that supply intracranial blood vessels and the meninges, also known as meningeal nociceptors. Although the mechanism underlying the triggering of such activation is not completely understood, our previous work indicates that the local activation of the inflammatory dural mast cells can provoke a persistent sensitization of meningeal nociceptors. Given the potential importance of mast cells to the pain of migraine it is important to understand which mast cell-derived mediators interact with meningeal nociceptors to promote their activation and sensitization. In the present study, we have used in vivo electrophysiological single-unit recording of meningeal nociceptors in the trigeminal ganglion of anesthetized rats to examine the effect of a number of mast cell mediators on the activity level and mechanosensitivity of meningeal nociceptors. We have found that that serotonin (5-HT), prostaglandin I2 (PGI2), and to a lesser extent histamine can promote a robust sensitization and activation of meningeal nociceptors, whereas the inflammatory eicosanoids PGD2 and leukotriene C4 are largely ineffective. We propose that dural mast cells could promote headache by releasing 5-HT, PGI2, and histamine.

Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: Therapeutic implications for migraine and other pains

Background Meningeal and other trigeminal nociceptors are thought to play important roles in the initiation of migraine headache. Currently, the only approved peripherally administered chronic migraine prophylactic drug is onabotulinumtoxinA. The purpose of this study was to determine how botulinum neurotoxin type A (BoNT-A) affects naïve and sensitized meningeal nociceptors. Material and methods Using electrophysiological techniques, we identified 43 C- and 36 Aδ-meningeal nociceptors, and measured their spontaneous and evoked firing before and after BoNT-A administration to intracranial dura and extracranial suture-receptive fields. Results As a rule, BoNT-A inhibited C- but not Aδ-meningeal nociceptors. When applied to nonsensitized C-units, BoNT-A inhibited responses to mechanical stimulation of the dura with suprathreshold forces. When applied to sensitized units, BoNT-A reversed mechanical hypersensitivity. When applied before sensitization, BoNT-A prevented development of mechanical hypersensitivity. When applied extracranially to suture branches of intracranial meningeal nociceptors, BoNT-A inhibited the mechanical responsiveness of the suture branch but not dural axon. In contrast, BoNT-A did not inhibit C-unit responses to mechanical stimulation of the dura with threshold forces, or their spontaneous activity. Discussion The study provides evidence for the ability of BoNT-A to inhibit mechanical nociception in peripheral trigeminovascular neurons. These findings suggest that BoNT-A interferes with neuronal surface expression of high-threshold mechanosensitive ion channels linked preferentially to mechanical pain by preventing their fusion into the nerve terminal membrane.

Sensitization of central trigeminovascular neurons: blockade by intravenous naproxen infusion

We have previously observed that migraine attacks impervious to triptan therapy were readily terminated by subsequent i.v. administration of the non-steroidal anti-inflammatory drug (NSAID) ketorolac. Since such attacks were associated with periorbital allodynia--a symptom of central sensitization--we examined whether infusion of the NSAID naproxen can block sensitization of central trigeminovascular neurons in the medullary dorsal horn, using in vivo single-unit recording in the rat. Topical exposure of the cerebral dura to inflammatory soup (IS) for 5 min resulted in a short-term burst of activity (<8 min) and a long-lasting (>120 min) neuronal hyper-responsiveness to stimulation of the dura and periorbital skin (group 1). Infusion of naproxen (1 mg/kg) 2 h after IS (group 1) brought all measures of neuronal responsiveness back to the baseline values recorded prior to IS, and depressed ongoing spontaneous activity well below baseline. When given preemptively 1 h before IS (group 2), naproxen blocked the short-term burst of activity and every long-term measure of neuronal hyper-responsiveness that was studied in the central neurons. The same preemptive treatment, however, failed to block IS-induced short-term bursts of activity in C-unit meningeal nociceptors (group 3). The results suggest that parenteral administration of naproxen, unlike triptan therapy, can exert direct inhibition over central trigeminovascular neurons in the dorsal horn. Though impractical as a routine migraine therapy, parenteral NSAID administration should be useful as a non-narcotic rescue therapy for migraine in the setting of the emergency department.

Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions.

&NA; The proinflammatory cytokine TNF‐&agr; has been shown to promote activation and sensitization of primary afferent nociceptors. The downstream signaling processes that play a role in promoting this neuronal response remain however controversial. Increased TNF‐&agr; plasma levels during migraine attacks suggest that local interaction between this cytokine and intracranial meningeal nociceptors plays a role in promoting the headache. Here, using in vivo single unit recording in the trigeminal ganglia of anesthetized rats, we show that meningeal TNF‐&agr; action promotes a delayed mechanical sensitization of meningeal nociceptors. Using immunohistochemistry, we provide evidence for non‐neuronal localization of the TNF receptors TNFR1 to dural endothelial vascular cells and TNFR2 to dural resident macrophages as well as to some CGRP‐expressing dural nerve fibers. We also demonstrate that meningeal vascular TNFR1 is co‐localized with COX‐1 while the perivascular TNFR2 is co‐expressed with COX‐2. We further report here for the first time that TNF‐&agr; evoked sensitization of meningeal nociceptors is dependent upon local action of cyclooxygenase (COX). Finally, we show that local application of TNF‐&agr; to the meninges evokes activation of the p38 MAP kinase in dural blood vessels that also express TNFR1 and that pharmacological blockade of p38 activation inhibits TNF‐&agr; evoked sensitization of meningeal nociceptors. Our study suggests that meningeal action of TNF‐&agr; could play an important role in the genesis of intracranial throbbing headaches such as migraine through a mechanism that involves at least part activation of non‐neuronal TNFR1 and TNFR2 and downstream activation of meningeal non‐neuronal COX and the p38 MAP kinase.

Sensitization of meningeal nociceptors : inhibition by naproxen

Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutaneous allodynia (manifestation of central sensitization) are readily terminated by intravenous administration of a non‐selective cyclooxygenase (COX) inhibitor. Evidence that sensitization of rat central trigeminovascular neurons was also terminated in vivo by non‐selective COX inhibition has led us to propose that COX inhibitors may act centrally in the dorsal horn. In the present study, we examined whether COX inhibition can also suppress peripheral sensitization in meningeal nociceptors. Using single‐unit recording in the trigeminal ganglion in vivo, we found that intravenous infusion of naproxen, a non‐selective COX inhibitor, reversed measures of sensitization induced in meningeal nociceptors by prior exposure of the dura to inflammatory soup (IS): ongoing activity of Aδ‐ and C‐units and their response magnitude to mechanical stimulation of the dura, which were enhanced after IS, returned to baseline after naproxen infusion. Topical application of naproxen or the selective COX‐2 inhibitor N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl]‐methanesulfonamide (NS‐398) onto the dural receptive field of Aδ‐ and C‐unit nociceptors also reversed the neuronal hyper‐responsiveness to mechanical stimulation of the dura. The findings suggest that local COX activity in the dura could mediate the peripheral sensitization that underlies migraine headache.

Local action of the proinflammatory cytokines IL-1β and IL-6 on intracranial meningeal nociceptors

Background: Peripheral nociceptive action of the proinflammatory cytokines IL-1β and IL-6 has been implicated in the pathogenesis of numerous pain syndromes. An increase in the level of these cytokines in jugular venous blood has been reported during migraine attacks, suggesting their potential involvement in mediating the intracranial headache of migraine. Methods: In this work we examined, using in vivo single-unit recording of meningeal nociceptors in the trigeminal ganglion of anesthetized rats, whether the peripheral actions of IL-1β and IL-6 can promote the activation and sensitization of nociceptors that innervate the intracranial meninges, two neural processes that are believed to play a key role in promoting the intracranial throbbing pain of migraine. Results: We found that meningeal application of IL-1β leads to the activation and mechanical sensitization of about 70% and 45% of the nociceptors respectively. In contrast, IL-6 was a very poor modulator of meningeal nociceptors’ response properties affecting overall only about 20% of the nociceptors. Conclusions: Our study provides for the first time in vivo electrophysiological evidence that meningeal action of IL-1β can promote the activation and increased mechanosensitivity of intracranial meningeal nociceptors and that IL-6 generally lacks these properties. Future studies are required to examine the mechanism that plays a role in mediating the nociceptive effects of IL-1β on meningeal nociceptors, which may serve as a target for migraine therapy.

Modulation of meningeal nociceptors mechanosensitivity by peripheral proteinase-activated receptor-2: the role of mast cells.

Inflammatory-related activation and sensitization of meningeal nociceptors is believed to play a key role in promoting the intracranial throbbing pain of migraine. We have shown recently that mast cell activation and various mast cell-derived inflammatory mediators can promote activation and sensitization of meningeal nociceptors. Mast cell tryptase has also been proposed to promote pain hypersensitivity by activating the proteinase-activated receptor 2 (PAR2) that is expressed on nociceptive neurons. In this study using in vivo single-unit recording in the trigeminal ganglion of anaesthetized rats, we found that local meningeal activation of PAR2 using the specific agonist SLIGRL-NH2 promoted sensitization of the threshold response while provoking desensitization of the suprathreshold responses. SLIGRL-NH2 also excited a subpopulation of meningeal nociceptors. Chronic mast cell depletion enhanced the sensitizing effects of PAR2 activation while curbing its desensitizing effects. Mast cell depletion did not change the PAR2-mediated excitatory effect. We propose that by enhancing the mechanical sensitivity of meningeal nociceptors local PAR2 activation could play a role in promoting the throbbing pain of migraine and that local mast cell degranulation may modulate such an effect.

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

Background Administration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be-discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields. Material and methods Using electrophysiological techniques, we identified 161 C- and 135 Aδ-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles. Results Seven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non-noxious mechanosensitivity of C-fibers or on responsiveness of Aδ-fibers to mechanical and chemical stimulation. Discussion This study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors’ responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A’s ability to act as a prophylactic.