Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.

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 Ϯ 4.6 min in trials in which activity returned to baseline, or Ͼ68 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 ϳ14 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.

To assess nonexperimental (NX) evaluation methods in the context of welfare, job training, and employment services programs, the authors reexamined the results of twelve case studies intended to replicate impact estimates from an experimental evaluation by using NX methods. They found that the NX methods sometimes came close to replicating experimentally derived results but often produced estimates that differed by policy-relevant margins, which the authors interpret as estimates of bias. Although the authors identified several study design factors associated with smaller discrepancies, no combination of factors would consistently eliminate discrepancies. Even with a large number of impact estimates, the positive and negative bias estimates did not always cancel each other out. Thus, it was difficult to identify an aggregation strategy that consistently removed bias while answering a focused question about earnings impacts of a program. They conclude that although the empirical evidence from this literature can be used in the context of training and welfare programs to improve NX research designs, it cannot on its own justify the use of such designs.

Objective-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).Methods-Stimulation of the cortex with pin prick or KCl granule was used to induce CSD. Neuronal activity was monitored in C1-2 using single-unit recording in anesthetized rats.Results-In 25 trigeminovascular neurons activated by CSD, mean firing rate (spikes/sec) increased from 3.6 ± 1.2 before CSD (baseline) to 6.1 ± 1.8 after CSD (p < 0.0001) for a period >13 min. Neuronal activity returned to baseline level after 30.0 ± 3.1 min in 14 units, and remained elevated for 66.0 ± 8.3 (22-108) min through the entire recording period in the other 11 units. Neuronal activation began within 0.9 ± 0.4 (0-2.5) min after CSD in 7 neurons located in laminae I-II, or after a latency of 25.1 ± 4.0 (7-75) min in 9 neurons located in laminae I-II, and 9 neurons located in laminae III-V. In 27 trigeminovascular neurons not activated by CSD, mean firing rate was 2.0 ± 0.7 at baseline and 1.8 ± 0.7 after CSD.Interpretation-We propose that CSD constitutes a nociceptive stimulus capable of activating peripheral and central trigeminovascular neurons that underlie the headache of migraine with aura.

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.