Acute stress shortens the time to onset of experimental allergic encephalomyelitis in SJL/J mice.
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Acute Disease↗
Biomedical subjects
T C Theoharides
Publications and source records attributed to T C Theoharides.
Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress.
PURPOSE: Mast cell activation and stress have been suggested as factors in the pathogenesis of interstitial cystitis, a painful disorder of the bladder that is diagnosed more frequently in women and characterized by increased urgency and frequency with absent infection. Intravesical sodium hyaluronate has been used to treat interstitial cystitis due to its possible replenishment of bladder glycosaminoglycans. We investigated the effect of sodium hyaluronate on the activation of bladder mast cell and release of proinflammatory mediators in the urine induced by acute immobilization stress in rats. MATERIALS AND METHODS: Using anesthesia a catheter was inserted in the bladder of 170 gm. female Sprague-Dawley rats. After emptying post-void residual urine a solution of normal saline, 0.08% or 0.4% sodium hyaluronate was introduced for 30 minutes. Each rat was allowed to recover from anesthesia and stressed for 30 minutes by confining it in a clear acrylic plastic immobilizer, while urine was continuously collected. Urinary histamine, rat mast cell protease-I and interleukin (IL)-6 were then determined. At the end of the experiments each rat was sacrificed by CO2 asphyxiation, and the bladder was removed and fixed with 4% paraformaldehyde. Frozen sections were stained with acidified toluidine blue, and the mast cell number and degree of activation were determined by granule extrusion and reduced cellular staining. RESULTS: Mean bladder mast cell activation plus or minus standard deviation in 6 control rats was 30.4% +/- 3.7% but it increased to 76.2% +/- 6.1% in 6 stressed animals (p = 0.0001). Intravesical administration of 0.4% sodium hyaluronate for 30 minutes in 6 rats before stress reduced mean bladder mast cell activation by 69.7% to 23.1% +/- 6.1% compared with stressed controls (p = 0.0003). However, compared to itself before stress there was no significant difference, indicating complete inhibition in 6 rats. Intravesical 0.08% sodium hyaluronate had a weaker inhibitory effect in 6 rats, decreasing mean degranulation by 22.5% to 59.1% +/- 7.6% (p = 0.02). In 6 rats stress increased the total mean amount of urinary rat mast cell protease-I by 271% from 0.14 +/- 0.09 to 0.52 +/- 0.17 ng. (p = 0.008). Pretreatment with 0.4% sodium hyaluronate reduced mean rat mast cell protease-I 80.8% compared with stressed controls (p = 0.008) and prevented any increase in response to stress in the same group of 8 rats with a mean pre-stress and post-stress level of 0.09 +/- 0.04 and 0.1 +/- 0.04 ng., respectively (p = 0.8). Acute stress increased mean urinary histamine in 6 rats 40.2% from 137.3 +/- 29.7 before to 193.7 +/- 7.6 ng./ml. after stress (p = 0.004). Pretreatment with 0.4% sodium hyaluronate reduced mean histamine 7.1% compared with stressed controls but completely prevented any increase in the same group of 8 rats, in which it was 174.5 +/- 23.1 before and remained 179.4 +/- 9.9 ng./ml. after stress (p = 0.75). Acute stress in 7 rats also increased the mean amount of IL-6 released in the urine by 31.5% from 775.9 +/- 69.2 to 1,021.1 +/- 93.3 pg./ml. (p = 0.007). Pretreatment with 0.4% sodium hyaluronate in 9 rats reduced mean IL-6 17% compared with stressed controls but again prevented any increase from baseline, since the value was 898.6 +/- 299.3 before and 824.4 +/- 196.4 pg./ml. after stress (p = 0.03). CONCLUSIONS: Immobilization stress induces bladder mast cell activation and the secretion of proinflammatory mediators, which are inhibited by sodium hyaluronate. Intravesical sodium hyaluronate may be a useful therapeutic option for interstitial cystitis, especially in patients with bladder mastocytosis who have symptom exacerbation with stress.
Administration, Intravesical↗
Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells.
Disruption of the blood-brain-barrier (BBB) is important in the pathophysiology of various inflammatory conditions of the central nervous system (CNS), such as multiple sclerosis (MS), in which breakdown of the BBB precedes any clinical or pathological findings. There is some evidence that relapsing-remitting MS attacks may be correlated with certain types of acute stressful episodes. Stress typically activates the hypothalamic-pituitary-adrenal (HPA) axis through the release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down regulate immune responses. However, acute stress also has pro-inflammatory effects that appear to be mediated through activation of mast cells. Here we show that acute stress by immobilization increased permeability of rat BBB to intravenous 99Technetium gluceptate (99Tc). This effect was statistically significant in the diencephalon and the cerebellum, while it was absent in the cerebral cortex where there are not mast cells. Immobilization stress also induced activation of mast cells in diencephalon, the site where most mast cells are found in the rat brain. Both BBB permeability and mast cell activation were inhibited by the 'mast cell stabilizer' disodium cromoglycate (cromolyn). These results expand the pathophysiology of mast cells and implicate them in CNS disorders, that may possibly be induced or exacerbated by stress.
Acute Disease↗
Mast cell involvement in interstitial cystitis: a review of human and experimental evidence.
Interstitial cystitis (IC) is a heterogeneous syndrome of unknown etiology. Altered bladder glycosaminoglycans lining and bladder mastocytosis have been documented in IC. The objective of this article is to critically examine the published data on bladder mastocytosis in clinical, experimental, and animal studies, with particular emphasis on morphologic evidence of mast cell increase and activation. The literature on bladder mastocytosis and mast cell activation in IC is critically reviewed with particular reference to staining methodology, tryptase immunoreactivity, and electron microscopy. Data from humans and animal models of IC are included. Mastocytosis in IC is best documented by tryptase immunocytochemical staining. Standard surgical stains such as Giemsa and toluidine blue routinely underestimate the degree of mastocytosis. Mast cells are 6- to 8-fold higher in the detrusor compared with controls in "classic IC," and 2- to 3-fold higher in "nonulcerative" IC. Detrusor mastocytosis occurs in both classic and nonulcer IC. Mucosal mast cell increase is present in nonulcerative IC. Mast cell activation without typical exocytosis occurs in the mucosa and submucosa. Activation of mast cells, irrespective of bladder location or degree of mastocytosis, is significant. Mast cell-derived vasoactive and proinflammatory molecules may contribute to the pathogenesis of IC.
Animals↗
Massive extracellular tryptase from activated bladder mast cells in interstitial cystitis.
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Biopsy↗
Non-invasive assessment of blood-brain barrier (BBB) permeability using a gamma camera to detect 99technetium-gluceptate extravasation in rat brain.
The blood-brain barrier (BBB) is a complex structure of endothelial cells, astroglia, pericytes, and perivascular macrophages enclosed by basal lamina. The BBB regulates the entry of blood-borne molecules and cells into the brain, but it is disrupted in various inflammatory conditions of the central nervous system (CNS). We previously showed that 30 min of immobilization stress increased 99technetium-gluceptate (99Tc) extravasation, measured by a gamma counter, in brain regions containing mast cells, an effect blocked by the mast cell stabilizer disodium cromoglycate [Brain Res. 888 (2001) 117]. Here we report the use of a gamma camera to assess BBB permeability by assessing 99Tc extravasation in the rat brain, during and following acute stress, without having to sacrifice the experimental animals. This method also allows for repeated experimentation on the same animal, since the half-life of 99Tc is only 6 h, and permits testing of potential inhibitors of BBB permeability.
Animals↗
Elevated interleukin-6 levels in patients with asymptomatic left ventricular systolic dysfunction.
BACKGROUND: Elevated interleukin-6 (IL-6) levels are present in patients with New York Heart Association (NYHA) class III and IV congestive heart failure (CHF) and are associated with a poor prognosis. We sought to determine whether elevated IL-6 levels are also present in patients with left ventricular (LV) dysfunction but without clinical symptoms. METHODS: Blood samples were obtained from the femoral artery of 58 patients who underwent cardiac catheterization for recognized clinical indications. In a subgroup of 44 patients, samples were also obtained from the femoral vein, the left main coronary artery, and the coronary sinus. Patients with prior coronary artery bypass surgery, recent acute coronary syndrome, or steroid therapy were excluded. All samples were obtained before heparin or contrast administration. IL-6 was measured by enzyme-linked immunosorbent assay and values are expressed in picograms per milliliter. RESULTS: Three groups of patients were identified: controls, no CHF, LV ejection fraction >/=0.55 (n = 32); asymptomatic LV systolic dysfunction, no CHF, LV ejection fraction <0.55 (n = 14); and CHF, pulmonary edema (n = 12). IL-6 levels were higher at all sampling sites in both the asymptomatic LV systolic dysfunction and CHF groups compared with controls with the IL-6 levels inversely related to LV ejection fraction. CONCLUSIONS: Elevated IL-6 levels are present in patients with LV dysfunction even in the absence of the clinical syndrome of CHF. These data suggest that IL-6 may be involved in the progression of subclinical LV dysfunction to clinical CHF. IL-6 may be a marker of patients at risk for progression to clinical CHF or a novel target for therapeutic intervention.
Female↗
Delayed inflammation in rat meninges: implications for migraine pathophysiology.
Nitric oxide (NO) has been implicated in migraine pathogenesis based on the delayed development of typical migraine headache 4-6 h after infusing the NO donor nitroglycerin [glyceryl trinitrate (GTN)] to migraineurs. Furthermore, inhibiting the synthesis of NO by treatment with a NO synthase (NOS) inhibitor attenuates spontaneous migraine headaches in 67% of subjects. Because NO has been linked to inflammation and cytokine expression, we investigated the delayed consequences of brief GTN infusion (30 min) on the development of meningeal inflammation in a rat model using doses relevant to the human model. We found dose-dependent Type II NOS [inducible NOS (iNOS)] mRNA upregulation in dura mater beginning at 2 h and an increase in the corresponding protein expression at 4, 6 and 10 h after infusion. Type II NOS immunoreactivity was expressed chiefly within resident meningeal macrophages. Consistent with development of a delayed inflammatory response, we detected induction of interleukin 1beta in dura mater at 2 and 6 h and increased interleukin 6 in dural macrophages and in rat cerebrospinal fluid at 6 h after GTN infusion. Myeloperoxidase-positive cells were rarely found. Leakage of plasma proteins from dural blood vessels was first detected 4 h after GTN infusion, and this was suppressed by administering a specific Type II NOS inhibitor [L-N(6)-(1-iminoethyl)-lysine (L-NIL)]. In addition to cytokine induction, macrophage iNOS upregulation and oedema formation after GTN infusion, dural mast cells exhibited granular changes consistent with secretion at 4 and 6 h. Because iNOS was expressed in dural macrophages following topical GTN, and in the spleen after intravenous injection, the data suggest that the inflammatory response is mediated by direct actions on the dura and does not develop secondary to events within the brain. Our findings point to the importance of new gene expression and cytokine expression as fundamental to the delayed response following GTN infusion, and support the hypothesis that a similar response develops in human meninges after GTN challenge.
Animals↗
Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress.
BACKGROUND: Recent evidence indicates that acute stress can precipitate a number of dermatological conditions, including alopecia areata. This effect may be mediated by corticotropin-releasing hormone (CRH) released locally in the skin from dorsal root ganglia or immune cells. CRH typically acts through activation of specific receptors that are either type 1 or types 2 alpha and 2 beta. CRH, or related peptides such as urocortin, could have proinflammatory effects directly or through activation of mast cells leading to destruction of the hair root. OBJECTIVES: To investigate the expression of CRH receptors on the affected skin of patients who developed alopecia areata following acute emotional stress. METHODS: Scalp skin biopsies were obtained from 1 normal volunteer and 3 patients after ring infiltration of the relevant site with lidocaine. The biopsies were frozen and were later processed for in situ hybridization for CRH receptors type 1 or types 2 alpha and 2 beta. Sections showing positive results were photographed. RESULTS: The skin from the normal volunteer showed weak background expression of all three receptor types. However, skin from the affected sites of all 3 patients studied showed intense expression only on the type 2 beta receptor around the hair follicles. CONCLUSION: Acute emotional stress may precipitate alopecia areata by activation of overexpressed type 2 beta CRH receptors around the hair follicles leading to intense local inflammation.
Adult↗
New agents for the medical treatment of interstitial cystitis.
Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterised by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Symptoms of IC are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells. Increasing evidence suggests that neurogenic inflammation and/or neuropathic pain is a major component of IC pathophysiology. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpolysulphate (PPS). New treatments focus on the combined use of drugs that modulate bladder sensory nerve stimulation (neurolytic agents), inhibit neurogenic activation of mast cells, or provide urothelial cytoprotection, together with new drugs with anti-inflammatory activity.
Analgesics↗
Sites of interleukin-6 release in patients with acute coronary syndromes and in patients with congestive heart failure.
This study examines the source of elevated interleukin-6 (IL-6) levels in patients with acute coronary syndrome (ACS) and congestive heart failure (CHF). IL-6 is elevated in the peripheral blood of patients with ACS and CHF, but it is not known if this proinflammatory cytokine is from a cardiac or extracardiac source. Blood samples were obtained from the femoral artery, femoral vein, left main coronary artery, and coronary sinus in 57 patients during cardiac catheterization. IL-6 levels from 12 patients with ACS and 12 patients with CHF were compared with the IL-6 levels in 33 patients who had neither of these clinical conditions. Median IL-6 levels in the peripheral and coronary circulation were a minimum fivefold higher in patients with ACS or CHF relative to control patients. An elevated transcardiac IL-6 gradient (coronary sinus-left main level) was present in patients with ACS (median 5.2; 25th and 75th percentiles 3.9 and 29.3 pg/ml, respectively) compared with control patients (median 0, -0.7 and 0.5 pg/ml; p < 0.001), but not in patients with CHF (median 0.4, -0.7 and 3.5 pg/ml; p = NS). Elevated IL-6 levels in patients with ACS derive from a cardiac source, presumably from "inflamed" coronary plaques and areas of myocardial necrosis, whereas elevated levels in patients with CHF are most likely the result of extracardiac production.
Adult↗
Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation.
Experimental allergic encephalomyelitis (EAE) has been used as an animal model for the human demyelinating disease multiple sclerosis (MS). In acute MS or EAE, early disruption in the integrity of the blood-brain-barrier (BBB) precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cells. We investigated the number and degree of activation of brain mast cells in EAE and the effect of the heterocyclic histamine-1 receptor antagonist hydroxyzine, a piperazine compound known to also block mast cells. Acute EAE was induced in Lewis rats by immunization with whole guinea pig spinal cord homogenate and complete Freund's adjuvant (CFA). A second group of animals were treated orally with hydroxyzine for one day before immunization and then continuously for 14 days. Control rats were treated with CFA or hydroxyzine alone. The clinical progression of EAE was assessed on days 10, 12 and 14 after immunization. The number of metachromatic mast cells and the degree of degranulation was assessed in the thalamus with light microscopy. At day 14, there was a three-fold increase in the number of brain mast cells with EAE, as compared to controls. These cells were positive for the immunoglobulin E binding protein (FcepsilonRI), while those from control rats were not. Over 40% of all thalamic mast cells studied in EAE showed partial staining or extruded secretory granule indicative of secretion. Hydroxyzine treatment inhibited (p<0.05) the progression and severity of EAE by 50% and the extent of mast cell degranulation by 70% (p<0.05). These findings indicate that brain mast cells are associated with EAE development and that inhibition of their activation correlates positively with the clinical outcome.
Animals↗
Effect of an antioxidant (quercetin) on sodium-lauryl-sulfate-induced skin irritation.
Quercetin is a bioflavonoid with antioxidant and anti-inflammatory activity. The purpose of this study was to examine the effect of quercetin on acute skin irritation, with special interest in the skin barrier function recovery. Acute irritant contact dermatitis was induced in 15 patients by 24-h occlusion of 2% sodium lauryl sulfate (SLS) (day (D) 1). The influence of application on SLS-irritated skin of topical quercetin for 5 consecutive Ds, compared to vehicle and controls, was studied. Parameters measured were transepidermal water loss (TEWL) and erythema index. Final measurements were taken on D 7 after a 1-D rest period. TEWL and the erythema index continued to rise 2 D after application of SLS and 1 D after treatment with quercetin, vehicle or controls. Both TEWL and erythema values at D 7 did not return to values before the SLS barrier disruption at all the test sites. Therefore, quercetin topically applied after induction of irritant contact dermatitis does not appear to increase the recovery of barrier function and erythema caused by SLS.
Administration, Cutaneous↗
Chondroitin sulphate inhibits connective tissue mast cells.
1. Mast cells derive from the bone marrow and are responsible for the development of allergic and possibly inflammatory reactions. Mast cells are stimulated by immunoglobulin E (IgE) and specific antigen, but also by a number of neuropeptides such as neurotensin (NT), somatostatin or substance P (SP), to secrete numerous pro-inflammatory molecules that include histamine, cytokines and proteolytic enzymes. 2. Chondroitin sulphate, a major constituent of connective tissues and of mast cell secretory granules, had a dose-dependent inhibitory effect on rat peritoneal mast cell release of histamine induced by the mast cell secretagogue compound 48/80 (48/80). This inhibition was stronger than that of the clinically available mast cell 'stabilizer' disodium cromoglycate (cromolyn). Inhibition by chondroitin sulphate increased with the length of preincubation and persisted after the drug was washed off, while the effect of cromolyn was limited by rapid tachyphylaxis. 3. Immunologic stimulation of histamine secretion from rat connective tissue mast cells (CTMC) was also inhibited, but this effect was weaker in umbilical cord-derived human mast cells and was absent in rat basophilic leukemia (RBL) cells which are considered homologous to mucosal mast cells (MMC). Oligo- and monosaccharides were not as effective as the polysaccharides. 4. Inhibition, documented by light and electron microscopy, involved a decrease of intracellular calcium ion levels shown by confocal microscopy and image analysis. Autoradiography at the ultrastructural level showed that chondroitin sulphate was mostly associated with plasma and perigranular membranes. 5. Chondroitin sulphate appears to be a potent mast cell inhibitor of allergic and nonimmune stimulation with potential clinical implications.
Animals↗
Cloning and cellular localization of the rat mast cell 78-kDa protein phosphorylated in response to the mast cell "stabilizer" cromolyn.
Disodium cromoglycate (cromolyn) inhibits mast cell secretion, but its mechanism has not been elucidated. One possibility is the phosphorylation of a 78-kDa mast cell protein, two fragments of which are homologous to moesin, a member of the ezrin, radixin, moesin family. These proteins appear to be involved in signal transduction by regulating functional associations between the cell surface and the cytoskeleton. Moesin cDNA was cloned from rat basophil leukemia cells, which are similar to mucosal mast cells, and polyclonal antiserum was prepared against recombinant moesin expressed in Escherichia coli. Moesin phosphorylated in mast cells treated with cromolyn shifted from the soluble to the precipitable fraction and associated with Sepharose-linked beta-actin. Recombinant moesin also associated with Sepharose-linked beta-actin, and so did purified RBL moesin, but only if the latter was first denatured. Moesin thus appears to have actin binding sites that are not exposed under normal conditions but may become available by in vivo phosphorylation or by denaturation. Immunocytochemistry using confocal microscopy showed moesin to be primarily localized on the inner aspect of the plasma membrane and around secretory granules. Double immunocytochemistry for moesin and actin colocalized them in most areas. Ultracryoimmunoelectron microscopy to preserve the antigenicity of moesin identified the protein close to the plasma and secretory granule membranes. Cromolyn appeared to induce clustering of moesin around secretory granules. It is hypothesized that conformational changes of moesin, regulated by phosphorylation/dephosphorylation, may lead to positional rearrangements with respect to the membrane/cytoskeleton that could possibly regulate mast cell secretion.
Actins↗
Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis.
PURPOSE: Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory molecules in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses. An example is interstitial cystitis, which is a sterile painful bladder disorder that has been associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Pentosanpolysulfate is a synthetic, sulfated polysaccharide that has been approved for the treatment of interstitial cystitis on the premise that it may replenish the defective glycosaminoglycan layer. We hypothesize that pentosanpolysulfate may also have an additional or alternate action on bladder mast cells. We report that pentosanpolysulfate has a powerful dose dependent inhibitory effect on mast cell release of histamine induced by the mast cell secretagogue compound 48/80. MATERIALS AND METHODS: Inhibition of mast cell secretion was documented by light and electron microscopy and extended to stimulation by substance P or IgE and antigen. RESULTS: The inhibition was more potent than that seen with the clinically available mast cell stabilizer disodium cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was apparent within 1 minute, was unaffected by the length of pre-incubation and persisted after the drug was washed off. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leukemia cells, pentosanpolysulfate inhibited histamine secretion from both. Confocal microscopy using a calcium indicator dye showed that pentosanpolysulfate decreased intracellular calcium ion levels. CONCLUSIONS: Pentosanpolysulfate appears to be a potent inhibitor of allergic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.
Animals↗
The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.
Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.
Animals↗
Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo.
Mast cells derive from a distinct bone marrow precursor and mature in tissues under the influence of stem cell factor, nerve growth factor (NGF) and certain interleukins. Intracranial mast cells first appear in the meninges and are located perivascularly close to neurons. They can be activated by antidromic stimulation of the trigeminal nerve, as well as by acute immobilization stress. Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly potent in stimulating mast cell release of vasoactive, inflammatory and nociceptive molecules. These findings have suggested that mast cells may be involved in neuroinflammatory conditions, such as migraines. In this study, dura mast cells were shown to have characteristics of connective tissue mast cells (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP-I). Mast cells were localized close to SP-positive neurons immunocytochemically and mast cell-neuron contacts were also documented using scanning electron microscopy. Dura stimulated by SP and carbachol in situ released histamine. Preincubation of dura with estradiol slightly augmented histamine release by SP, an effect possibly mediated through estrogen receptors identified on dura mast cells. Acute stress by immobilization led to dura mast cell degranulation which was prevented by pretreatment with a neutralizing antibody to CRH or a CRH receptor antagonist. The present results further clarify the biology of intracranial mast cells and support their involvement in the pathophysiology of migraines which are precipitated or worsened by stress.
Animals↗