Localization of COX-1 and COX-2 in the intracranial dura mater of the rat

Zhang, Xichun; Kainz, Vanessa; Jakubowski, Moshe; Burstein, Rami; Strassman, Andrew M.; Levy, Dan

doi:10.1016/j.neulet.2009.01.032

Cited by 19 publications

(14 citation statements)

References 27 publications

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“…Despite the lack of TNFR1 immunoreactivity in dural axons, we detected its expression in dural blood vessels. Dural vascular TNFR1 expression was also co-localized with vimentin, a marker that identifies dural vascular endothelial cells [47] and is in agreement with its expression on vascular endothelial cells from other tissues [21]. Dural vascular TNFR1 was also co-localized with COX-1 which we have shown recently also localized to dural vascular endothelial cells [47].…”

Section: Discussionsupporting

confidence: 70%

“…TNFR1 immunolabeling was predominantly localized to the dural vasculature with medium and small dural blood vessels showing the highest expression. As figure 5 demonstrates, TNFR1 was co-localized in dural vessels with vimentin, indicating its presence in endothelial cells [47]. Vascular TNFR1 was also co-labeled with vascular COX-1.…”

Section: Resultsmentioning

confidence: 99%

“…Following blocking, specimen were incubated for 48 h at 4 °C with primary antibodies against TNFR1 (mouse monoclonal antibody raised against amino acids 30–301 mapping within the extracellular domain of TNFR1, SC-8436, 1:250, Santa Cruz Biotechnology) or against TNFR2 (goat polyclonal antibody raised against the C-terminus of TNFR2, SC-1072, 1:500, Santa Cruz Biotechnology). To examine dural cell types that might express TNFR1 and TNFR2, double labeling were conducted in conjunction with another antibody to detect: 1) peripheral nerve fibers (Peripherin, Rabbit polyclonal antibody, 1:1000, Ab1530, Millipore, or CGRP, Rabbit polyclonal antibody, 1:1000 T-4032, bachem), 2) dural vascular endothelial cells (vimentin, Rabbit polyclonal antibody, 1:250, SC-5565, Santa Cruz biotechnology), or 3) resident macrophages (mouse monoclonal antibody, CD163, clone ED2, 1:500, MCA342, Serotec) as we described earlier [47]. For all indirect immunofluorescence, Alexa 594 and/or Alexa 488- conjugated secondary antibodies (1:200, Invitrogen,) were employed.…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Kainz

Burstein

et al. 2011

Pain

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127

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The proinflammatory cytokine TNF-alpha 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-alpha 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-alpha 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-alpha evoked sensitization of meningeal nociceptors is dependent upon local action of cyclooxygenase (COX). Finally, we show that local application of TNF-alpha 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-alpha evoked sensitization of meningeal nociceptors. Our study suggests that meningeal action of TNF-alpha could play an important role in the genesis of intracranial throbbing headaches such as migraine through a mechanism that involves at least partly activation of non-neuronal TNFR1 and TNFR2 and downstream activation of meningeal non-neuronal COX and the p38 MAP kinase.

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Section: Discussionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Zhang

Kainz

Burstein

et al. 2011

Pain

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127

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“…The co-localization of COX-2 and CGRP is observed in some dural nerve fibers, which suggests that COX-2 may be related to the function of CGRP. 39 It has been shown that CGRP release is mediated by a COX-2-dependent pathway and COX-2 expression in trigeminal ganglion cells could contribute to the development of pain in trigeminally mediated headaches. 40,41 The attenuation of CGRP release by COX-2 inhibition could at least in part explain the mechanism of COX inhibitors as migraine therapy.…”

Section: Discussionmentioning

confidence: 99%

<p>Electroacupuncture Inhibits Hyperalgesia by Alleviating Inflammatory Factors in a Rat Model of Migraine</p>

Zhao¹,

Liu²,

Xu³

et al. 2020

JPR

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Objective: Acupuncture has a therapeutic effect similar to that of prophylactic drugs and can be considered a treatment option for migraineurs. However, the mechanism of acupuncture treatment's effect on migraine is uncertain. An approach based on anti-inflammatory effects is an important treatment strategy for migraine because non-steroidal anti-inflammatory drugs (NSAIDs) are usually used during migraine attacks. Meningeal inflammation is thought to be responsible for the activation of the trigeminovascular system. Our previous study found that electroacupuncture (EA) decreased neurogenic inflammation mediator expression in the trigeminal ganglion (TG) and alleviated hyperalgesia. The present study examined whether EA would inhibit hyperalgesia by alleviating neurogenic inflammatory factors.Methods: A rat model of migraine was established using dural electrical stimulation (DES). Five groups were analyzed in this study. The Model group received DES three times to mimic migraine attacks, a Control group had sham DES, and three groups received electroacupuncture after DES: a Non-Acu group at a non-acupuncture point, a GB20 group at GB20, and a GB20/34 group at GB20 and GB34 acupuncture points. We evaluated mechanical hyperalgesia using an electronic von Frey esthesiometer in the awake state. After sacrifice, the dura mater was analyzed using immunofluorescence. Serum calcitonin gene-related peptide, cyclooxygenase-2, brainderived neurotrophic factor, IL-1β, IL-6, and TNF levels were determined using enzymelinked immunosorbent assays to evaluate the anti-inflammatory effect of acupuncture. Results: After repeated DES, we observed facial and hind paw mechanical hyperalgesia, which was inhibited by electroacupuncture. Electrical stimulation increased the number of mast cells and macrophages and serum levels of inflammatory factors. GB20 and GB20/34 electroacupuncture significantly decreased the number of mast cells and macrophages and serum levels of inflammatory factors. Moreover, electroacupuncture at GB20/34 was superior to that at GB20 alone in inhibiting hyperalgesia and alleviating inflammatory factors. Conclusion: Electroacupuncture inhibits DES-induced hyperalgesia by alleviating inflammatory factors. Inhibition of dural mast cells, macrophages, and serum inflammatory factors may be one of the mechanisms involved in acupuncture treatment's effect on migraine.

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“…One major process that might contribute to headache triggering is sterile meningeal inflammation and the ensuing persistent activation of primary afferent nociceptive neurons that innervate the meninges and their related large blood vessels. The dural layer of the meninges is the one most heavily innervated by nociceptive afferents and is also highly populated by immune cells, including macrophages, dendritic cells and mast cells (MCs) (4, 5). Dural MCs are of particular interest because of their close proximity to dural nociceptors (6, 7).…”

Section: Introductionmentioning

confidence: 99%

Influence of sex, estrous cycle, and estrogen on intracranial dural mast cells

Boes

Levy

2012

Cephalalgia

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Background The frequency of migraine headaches is higher in women than in men and in susceptible women attacks are related to changes in ovarian hormone levels. Intracranial mast cells (MCs) are likely to play a role in migraine headache genesis, and changes in the dural MC population might influence headache susceptibility. The present study thus tested the hypothesis that sex and ovarian hormones influence the density and phenotypic makeup of dural MCs. Methods Histochemistry combined with quantitative analyses was employed to investigate sex differences, estrous cycle and ovarian hormone influences on dural MCs density, phenotype and degranulation level in males and females rats. Results Our data show that in female rats, dural MC density fluctuates during the estrous cycle and is overall higher than in males. In ovariectomized rats, estradiol, but not progesterone, promoted an increase in dural MCs density. This effect was abolished by a splenectomy, suggesting estrogen-related recruitment of MCs from the spleen. Finally, our data suggest that the phenotypic make up of dural MCs, which represents the level of cellular maturity, is also governed by changes in estrogen levels. Conclusions Given the potential role of dural MCs in triggering headache, our data suggest that estrogen-related modulation of dural MC density and phenotypic makeup could play a role in mediating the higher frequency and severity of headaches, such as migraine, in women.

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Localization of COX-1 and COX-2 in the intracranial dura mater of the rat

Cited by 19 publications

References 27 publications

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

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

<p>Electroacupuncture Inhibits Hyperalgesia by Alleviating Inflammatory Factors in a Rat Model of Migraine</p>

Influence of sex, estrous cycle, and estrogen on intracranial dural mast cells

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