Mast cell degranulation activates a pain pathway underlying migraine headache. Pain

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard Institutes of Medicine, Room 856, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Pain (Impact Factor: 5.21). 08/2007; 130(1-2):166-76. DOI: 10.1016/j.pain.2007.03.012
Source: PubMed

ABSTRACT 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.

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Available from: Vanessa Kainz, Feb 20, 2014
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    • "Histamine, a major amine released from mast cells, is known to induce a migraine-like pain upon infusion into test subjects previously diagnosed with migraine [5]. Some migraine-associated symptoms, including the characteristic pain, could therefore stem from the activation of meningeal mast cells and aseptic inflammation initiated by histamine release [6]. However, local administration of calcitonin gene-related peptide (CGRP), which is a sensory neuropeptide in the dura mater and a known migrainogenic substance [7], results only in vasodilatation [8]. "
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    ABSTRACT: Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine. A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E2 (PGE2), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean Emax(%) at the highest concentration of each substance to the Emax(%) of NaCl buffer. In the human experiments, all substances except PACAP-38 had an Emax(%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF2alpha, similar tendencies were seen. When the pre-contraction was switched to K+ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries. Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution.
    The Journal of Headache and Pain 04/2014; 15(1):22. DOI:10.1186/1129-2377-15-22 · 2.80 Impact Factor
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    • "Therefore, in hyper-innervated allergic sites in Ox-challenged labia, mast cell-neuron synapses can potentially regulate changes in pain sensitivity in the periphery. Systemic mast cell degranulation can be followed by changes in c-fos and pERK expression in the spinal cord [48,49], indicating that mast cells may contribute to central sensitization in nociceptive signaling. "
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    ABSTRACT: The interplay among pain, allergy and dysregulated inflammation promises to yield significant conceptual advances in immunology and chronic pain. Hapten-mediated contact hypersensitivity reactions are used to model skin allergies in rodents but have not been utilized to study associated changes in pain perception in the affected skin. Here we characterized changes in mechanical hyperalgesia in oxazolone-sensitized female mice challenged with single and repeated labiar skin exposure to oxazolone. Female mice were sensitized with topical oxazolone on their flanks and challenged 1-3 times on the labia. We then measured mechanical sensitivity of the vulvar region with an electronic pressure meter and evaluated expression of inflammatory genes, leukocyte influx and levels of innervation in the labiar tissue. Oxazolone-sensitized mice developed vulvar mechanical hyperalgesia after a single labiar oxazolone challenge. Hyperalgesia lasted up to 24 hours along with local influx of neutrophils, upregulation of inflammatory cytokine gene expression, and increased density of cutaneous labiar nerve fibers. Three daily oxazolone challenges produced vulvar mechanical hyperalgesic responses and increases in nerve density that were detectable up to 5 days post-challenge even after overt inflammation resolved. This persistent vulvar hyperalgesia is resonant with vulvodynia, an understudied chronic pain condition that is remarkably prevalent in 18-60 year-old women. An elevated risk for vulvodynia has been associated with a history of environmental allergies. Our pre-clinical model can be readily adapted to regimens of chronic exposures and long-term assessment of vulvar pain with and without concurrent inflammation to improve our understanding of mechanisms underlying subsets of vulvodynia and to develop new therapeutics for this condition.
    PLoS ONE 10/2013; 8(10):e78673. DOI:10.1371/journal.pone.0078673 · 3.23 Impact Factor
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    • "They were divided into two morphological types: ''small dark'' – without apoptosis and ''large light'' – with apoptosis. (B) Number and degranulation of mastocytes (Levy et al., 2007). The cells were counted in five adjacent fields (0.47 mm 2 ) beginning from the site of transection. "
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    ABSTRACT: Abstract The purpose of the study was to examine the influence of the spatial variable magnetic field (induction: 150-300 µT, 80-150 µT, 20-80 µT; frequency 40 Hz) on neuropathic pain after tibial nerve transection. The experiments were carried out on 64 male Wistar C rats. The exposure of animals to magnetic field was performed 1 d/20 min., 5 d/week, for 28 d. Behavioural tests assessing the intensity of allodynia and sensitivity to mechanical and thermal stimuli were conducted 1 d prior to surgery and 3, 7, 14, 21 and 28 d after the surgery. The extent of autotomy was examined. Histological and immunohistochemical analysis was performed. The use of extremely low-frequency magnetic fields of minimal induction values (20-80 µT/40 Hz) decreased pain in rats after nerve transection. The nociceptive sensitivity of healthy rats was not changed following the exposition to the spatial magnetic field of the low frequency. The results of histological and immunohistochemical investigations confirm those findings. Our results indicate that extremely low-frequency magnetic field may be useful in the neuropathic pain therapy.
    Electromagnetic Biology and Medicine 06/2013; 33(1). DOI:10.3109/15368378.2013.783849 · 1.19 Impact Factor
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