Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

Amrutkar, Dipak Vasantrao; Ploug, K.B.; Olesen, Jes; Jansen‐Olesen, Inger

doi:10.1016/j.neuroscience.2010.10.032

Cited by 41 publications

(32 citation statements)

References 41 publications

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“…If we assume that Ca 2+ influx through P/Q- and L-type Ca 2+ channels controls the release of CGRP, then our findings here contrast those of Amrutkar et al . (2011), who found that block of P/Q- and L-type Ca 2+ channel subtypes each decreased 60mM potassium-induced CGRP release (Amrutkar et al, 2011). The differences between the two studies may be due to the different stimulation protocols and/or the different concentrations of the Ca 2+ channel antagonists used (Sidach and Mintz, 2000).…”

Section: Discussioncontrasting

confidence: 99%

“…Although T-type Ca 2+ channels are thought to play a central role in peripheral pain processing, where they are believed to regulate subthreshold excitability in the peripheral nociceptive fibres, they are not thought to control neurotransmitter release (Iftinca and Zamponi, 2009; Jevtovic-Todorovic and Todorovic, 2006; Todorovic and Jevtovic-Todorovic, 2006, 2007, 2011). Consistent with this, it was recently shown that T-type Ca 2+ channels did not contribute to high potassium-induced CGRP release measured by an enzyme-linked immunoassay in an ex vivo rat dural-skull preparation similar to the mouse preparation used in our study (Amrutkar et al, 2011). It is again interesting to speculate on the development of novel antimigraine therapeutics.…”

Section: Discussionsupporting

confidence: 91%

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Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres

2012

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The selective 5-HT1 receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5HT1 receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca2+ transients. Pre-application of the 5-HT1 antagonist GR127935 or the selective 5-HT1D antagonist BRL 15572 prevented inhibition while the selective 5-HT1B antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT1D receptor subtype. Sumatriptan inhibition of the action potential evoked Ca2+ signaling was mediated selectively through N-type Ca2+ channels. Although the T-type Ca2+ channel accounted for a greater proportion of the Ca2+ signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca2+ channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5HT1 receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 91%

Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres

2012

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“…Change in resting membrane potential is considered an important mechanism underlying the sensitisation of dural afferents evoked by inflammatory mediators leading to increased basal CGRP release (31). CGRP release induced by high KCl concentration requires the opening of voltage-gated calcium channels (37). The activity and/or expression of these channels may also be influenced by persistently elevated IL-1b and IL-6 levels possibly contributing to reduced CGRP release upon neuronal depolarisation with KCl (38).…”

Section: Discussionmentioning

confidence: 99%

Diet-induced obesity alters dural CGRP release and potentiates TRPA1-mediated trigeminovascular responses

et al. 2016

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Background Clinical studies suggest a link between obesity and the primary headache disorder migraine. In our study we aimed to reveal the effect of obesity on meningeal nociceptor function in rats receiving a high-fat, high-sucrose diet. Methods Transient receptor potential ankyrin 1 (TRPA1) receptor activation-induced changes in meningeal blood flow, release of calcitonin gene-related peptide (CGRP) from trigeminal afferents and TRPA1 protein expression in the trigeminal ganglia were measured in control and obese rats. Metabolic parameters of the animals were assessed by measuring glucose and insulin homeostasis as well as plasma cytokine concentrations. Results The present experiments revealed an enhanced basal and TRPA1 receptor agonist-induced CGRP release from meningeal afferents of obese insulin-resistant rats and an attenuated CGRP release to potassium chloride. Obesity was also associated with an augmented vasodilatation in meningeal arteries after dural application of the TRPA1 agonist acrolein, a reduction in TRPA1 protein expression in the trigeminal ganglia and elevations in circulating proinflammatory cytokines IL-1β and IL-6 in addition to increased fasting blood glucose and insulin concentrations. Conclusions Our results suggest trigeminal sensitisation as a mechanism for enhanced headache susceptibility in obese individuals after chemical exposure of trigeminal nociceptors.

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“…It is possible that other (i.e., P/Q- or L-type [75]) voltage-gated calcium channels may contribute to the Ca 2+ influx in TGs. Nevertheless, CGRP release from TG neurons could be inhibited with ω-conotoxin, the CaV2.2 blocker, but not by blockers of other voltage-gated calcium channels [2]. Additionally, ( S )-LCM significantly decreased capsaicin-evoked CGRP release from dural afferents to a degree similar to that observed in DRG cells, which is consonant with our previous finding of inhibition of capsaicin-triggered Ca 2+ influx by ( S )-LCM [51], thus validating the feasibility of indirect targeting CaV2.2, via CRMP2, as a novel means to curb CGRP release from the dura, a possible site of action relevant to migraine.…”

Section: Discussionmentioning

confidence: 99%

“…CaV2.2 activity controls neuropeptide release [48], and more specifically CGRP, in the peripheral nervous system [8; 45; 58] including trigeminal ganglia (TG) [1; 2] and dura mater [2]. Additionally, CaV2.2 is a major determinant of nociceptive signaling from the dura to the trigeminal nucleus caudalis [23; 65], thus placing the channel in a critical position to contribute to headache-related pain transmission.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of (S)-lacosamide in preclinical models of cephalic pain

Moutal

Eyde

Telemi

et al. 2016

PR9

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Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have suboptimal efficacy, and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective, but small molecule antagonists have not been advanced because of toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel “druggable” target for inhibiting CGRP release and for potential relevance for treatment of migraine pain. Collapsin response mediator protein 2 has been demonstrated to regulate N-type voltage-gated Ca2+ channel activity and Ca2+-dependent CGRP release in sensory neurons. The coexpression of CRMP2 with N-type voltage-gated Ca2+ channel and CGRP in trigeminal ganglia (TGs) sensory neurons suggested the possibility of a novel approach to regulate CGRP release in the trigeminal system. Screening protocols surprisingly revealed that (S)-lacosamide ((S)-LCM), an inactive analog of the clinically approved small molecule antiepileptic drug (R)-lacosamide (Vimpat), inhibited CRMP2 phosphorylation by cyclin-dependent kinase 5 in rat TG slices and decreased depolarization-evoked Ca2+ influx in TG cells in culture. (S)-LCM significantly blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat in ex vivo cranial cup preparation. Additionally, cephalic and extracephalic cutaneous allodynia induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators, was inhibited by oral administration of (S)-LCM. The confirmation of CRMP2 as an upstream mediator of CGRP release, together with the brain penetrance of this molecule suggests (S)-LCM as a potential therapy for acute migraine.

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Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

Cited by 41 publications

References 41 publications

Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres

Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres

Diet-induced obesity alters dural CGRP release and potentiates TRPA1-mediated trigeminovascular responses

Efficacy of (S)-lacosamide in preclinical models of cephalic pain

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