Characterization of a mouse model of headache

Huang, Delin; Ren, Lynn Y.; Qiu, Chang Shen; Liu, Ping; Peterson, Jonathan M.; Yanagawa, Yuchio; Cao, Yu Qing

doi:10.1097/j.pain.0000000000000578

Cited by 32 publications

(28 citation statements)

References 71 publications

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“…The primary goal of this study was to measure whether commonly used inflammatory agents that have been applied to the cranial dura of rats and lately also in mice (30), namely 5-HT and PGE 2 , can pass through the dura and reach detectable levels in the CSF and CNS. In addition, we have attempted to estimate by extrapolation from these measurements the CSF and CNS levels that would be attained in behavioral studies that use dural application of higher concentrations and quantities of these inflammatory mediators as a headache-inducing stimulus, and to evaluate whether these estimated central levels would be expected to have behavioral or physiological effects, based on previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…For future studies with such models it would be of interest to determine which of the observed behavioral changes can be evoked by the lower concentrations that have been shown to be effective for activating and sensitizing meningeal nociceptors (6, 9). In addition, the possibility of central effects will be increased in studies that use mouse instead of rat (30), due to a higher transdural permeability (27). …”

Section: Discussionmentioning

confidence: 99%

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Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

et al. 2016

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Background Application of inflammatory mediators to the cranial dura has been used as a method to activate and sensitize neurons in the meningeal sensory pathway in preclinical behavioral studies of headache mechanisms. However, the relatively high concentrations and volumes used in these studies raise the question of whether the applied agents might pass through the dura to act directly on central neurons, thus bypassing the dural afferent pathway. Methods We used a radiolabeling approach to quantify the meningeal permeability of two of the inflammatory mediators, 5-HT and PGE2, when applied to the cranial dura as part of an inflammatory mixture used in preclinical headache models. Results Both agents could be detected in samples taken four hours after dural application in the cerebrospinal fluid (CSF) and, in measurements made only for PGE2, in the central nervous system (CNS) as well. Based on our measurements, we made estimates of the CSF and CNS levels that would be attained with the higher concentrations and volumes of 5HT and PGE2 that were exogenously applied in previous pre-clinical headache studies. These estimated levels were comparable to or larger than normal endogenous levels, potentially large enough to have physiological effects. Conclusions The finding that the cranial meninges are permeable to the two tested inflammatory mediators PGE2 and 5-HT raises some uncertainty about whether the behavioral changes observed in prior pre-clinical headache studies with these as well as other agents can be attributed entirely to the activation of dural nociceptors, particularly when the agents are applied at concentrations several orders of magnitude above physiological levels.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

et al. 2016

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“…The sequence of COX-1 linked to TXAS through a 10-aa linker (COX-1-10aa-TXAS) was produced by PCR and subcloning procedures using similar methods as previously described. [19][20][21][22] Through the PCR cloning method, the cDNA was successfully subcloned into the pcDNA 3.1(+) vectors between the two BamHl sites containing a cytomegalovirus early promoter. The correct inserted size of cDNA was confirmed by restriction enzyme digestion analysis and DNA sequencing.…”

Section: Engineering Of the Schec Cox-1-10aa-txas Cdna And Subcloningmentioning

confidence: 99%

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions

Ling

et al. 2019

J Cellular Molecular Medi

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Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure‐based enzymatic design, we have engineered a novel single‐chain hybrid enzyme complex (SCHEC), COX‐1‐10aa‐TXAS. We linked the C‐terminus of cyclooxygenase‐1 (COX‐1) to the N‐terminus of the thromboxane A2 (TXA2) synthase (TXAS), through a 10‐amino acid residue linker. This recombinant COX‐1‐10aa‐TXAS can effectively pass COX‐1–derived intermediate prostaglandin (PG) H2 (PGH2) to the active site of TXAS, resulting in an effective chain reaction property to produce the haemostatic prostanoid, TXA2, rapidly. Advantageously, COX‐1‐10aa‐TXAS constrains the production of other pro‐bleeding prostanoids, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), through reducing the common substrate, PGH2 being passed to synthases which produce aforementioned prostanoids. Therefore, based on these multiple properties, this novel COX‐1‐10aa‐TXAS indicated a powerful anti‐bleeding ability, which could be used to treat a variety of bleeding situations and could even be useful for bleeding prone situations, including nonsteroidal anti‐inflammatory drugs (NSAIDs)‐resulted TXA2‐deficient and PGI2‐mediated bleeding disorders. This novel SCHEC has a great potential to be developed into a biological haemostatic agent to treat severe haemorrhage emergencies, which will prevent the complications of blood loss and save lives.

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“…Here, we investigated whether endogenous TRESK activity regulates the generation of headache-related behaviors in mice (Huang et al, 2016). After recovery from craniectomy for 7 days, both WT and TRESK KO mice exhibited some spontaneous forepaw wiping and hindpaw We went on to ask whether loss of TRESK alters the likelihood to manifest headacherelated behaviors in mice.…”

Section: Dural Afferent Neurons From Tresk Ko Mice Show Higher Intrinmentioning

confidence: 99%

TRESK K⁺Channel Activity Regulates Trigeminal Nociception and Headache

Guo

Qiu

Jiang

et al. 2019

Preprint

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Although dominant-negative mutations of TRESK background K + channel have been reported in migraine patients, whether TRESK activity controls the generation of trigeminal pain, especially headache, is not established. We found that loss of TRESK in all trigeminal ganglia (TG) neurons preferentially increased the intrinsic excitability of small-diameter TG nociceptors that express neuropeptide CGRP or TRPM8 channels. Surprisingly, loss of TRESK increased the number of TG neurons expressing TRPV1 channels. In dorsal root ganglia neurons, neither the persistent outward current nor the intrinsic excitability was affected by the loss of TRESK.Compared with wild-type controls, TRESK knockout mice exhibited more robust trigeminal pain, especially headache-like behaviors; but displayed normal body and visceral pain responses.Our findings indicate that endogenous TRESK activity is required for trigeminal pain regulation.A substantial reduction of TRESK activity may selectively affect the functions of TG nociceptors, thereby increasing the susceptibility to migraine headache in humans.1 1 current is fully compensated in DRG neurons. Consequently, in either small IB4 − or small IB4 + DRG subpopulation, WT and KO neurons exhibit similar R in , rheobase, spike frequency as well as other passive and active electrophysiological properties (Figures 5C-F, Table 2). Our findings are inconsistent with a previous study reporting a reduction of total persistent outward currents and AP rheobase in DRG neurons from mice expressing non-functional TRESK channels (Dobler et al., 2007). More work is needed to resolve the discrepancy. It is possible that results differ based on the duration of time neurons are maintained in vitro after dissociation. Here, we recorded DRG neurons between 2-4 days in vitro (DIV), whereas in earlier work neurons were recorded between 11-14 DIV. It has been reported that WT DRG neurons cultured for 5 DIV exhibited altered K + channel expression and excitability (Dawes et al., 2018;Martinez-Espinosa et al., 2015).Taken together, we conclude that ubiquitous loss of TRESK in all TG and DRG neurons preferentially increases the intrinsic excitability of small IB4 − TG nociceptors that express CGRP and/or TRPM8, suggesting that the contribution of endogenous TRESK channel to PAN excitability is cell-type specific and is not determined by its expression pattern. Loss of TRESK selectively increases the number of capsaicin-responsive (Cap + ) neurons inthe IB4 − TG subpopulation.Here, we investigated whether loss of TRESK affect the responses of TG neurons to noxious stimuli, for example, exposure to capsaicin that selectively activates TRPV1 channels. We applied capsaicin (100 nM) to small-diameter TG neurons in culture and recorded their responses under current-clamp. In TG culture from adult WT mice, capsaicin elicited depolarization in 9 of Acosta, C., Djouhri, L., Watkins, R., Berry, C., Bromage, K., & Lawson, S. N. (2014). TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membr...

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Characterization of a mouse model of headache

Cited by 32 publications

References 71 publications

Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions

TRESK K⁺Channel Activity Regulates Trigeminal Nociception and Headache

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Characterization of a mouse model of headache

Cited by 32 publications

References 71 publications

Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A2 and exhibiting powerful anti‐bleeding functions

TRESK K+Channel Activity Regulates Trigeminal Nociception and Headache

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A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions

TRESK K⁺Channel Activity Regulates Trigeminal Nociception and Headache