The calcitonin gene-related peptide receptor antagonist MK-8825 decreases spinal trigeminal activity during nitroglycerin infusion

Abstract

BackgroundCalcitonin gene-related peptide (CGRP) and nitric oxide (NO) are regarded as key mediators in migraine and other primary headaches. Migraineurs respond to infusion of nitroglycerin with delayed headaches, and inhibition of CGRP receptors has been shown to be effective in migraine therapy. In animal experiments nitrovasodilators like nitroglycerin induced increases in spinal trigeminal activity, which were reversed after inhibition of CGRP receptors. In the present study we asked if CGRP receptor inhibition can also prevent spinal trigeminal activity induced by nitroglycerin.MethodsIn isoflurane anaesthetised rats extracellular recordings were made from neurons in the spinal trigeminal nucleus with meningeal afferent input. The non-peptide CGRP receptor inhibitor MK-8825 (5 mg/kg) dissolved in acidic saline (pH 3.3) was slowly infused into rats one hour prior to prolonged glyceryl trinitrate (nitroglycerin) infusion (250 μg/kg/h for two hours).ResultsAfter infusion of MK-8825 the activity of spinal trigeminal neurons with meningeal afferent input did not increase under continuous nitroglycerin infusion but decreased two hours later below baseline. In contrast, vehicle infusion followed by nitroglycerin was accompanied by a transient increase in activity.ConclusionsCGRP receptors may be important in an early phase of nitroglycerin-induced central trigeminal activity. This finding may be relevant for nitroglycerin-induced headaches.

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

“…MK8825 binds to the CGRP receptors, RAMP1 and CLR, in the trigeminal ganglia to inhibit binding. 77 MK8825 blocks NO-induced neuronal activation in the caudal brainstem, where the first synapse is formed by the central terminal of the trigeminal ganglia. 77 Sumatriptan is a triptan-class medication and inhibits the release of CGRP from the central afferents of the trigeminal ganglia in addition to being a 5HT1B/1D receptor agonist with a role in descending pain modulation.…”

“…77 MK8825 blocks NO-induced neuronal activation in the caudal brainstem, where the first synapse is formed by the central terminal of the trigeminal ganglia. 77 Sumatriptan is a triptan-class medication and inhibits the release of CGRP from the central afferents of the trigeminal ganglia in addition to being a 5HT1B/1D receptor agonist with a role in descending pain modulation. CGRP expression is minimal in the control brain tissue (A, C, and E), whereas substantial CGRP immunoreactive product is visualized in the pial layers in the CCI-injured brain (B, D, and F).…”

Blockade of 5‐HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine

“…The model of trigemino‐durovascular nociception, employed in the presented work, implies the use of anaesthetised animals the nociceptive status of which may be considered physiologically normal, that is to say, not altered by any sensitisation procedure. However, there are variations to this model that involve sensitisation of neurons within the trigemino‐thalamo‐cortical pathway induced either by local application of a mixture of inflammatory mediators (ie, “inflammatory soup”) to the dura mater or systemic administration of nitro‐glycerine . This approach allows mimicking of the sustained increase in excitability of the peripheral and central components of the trigeminovascular system – the neural process which is peculiar to migraine and shapes its pathogenesis and clinical characteristics …”

“…However, there are variations to this model that involve sensitisation of neurons within the trigemino-thalamo-cortical pathway induced either by local application of a mixture of inflammatory mediators (ie, "inflammatory soup") to the dura mater 37,38 or systemic administration of nitro-glycerine. 39,40 This approach allows mimicking of the sustained increase in excitability of the peripheral and central components of the trigeminovascular system -the neural process which is peculiar to migraine and shapes its pathogenesis and clinical characteristics. 1 Nevertheless, the analysis of numerous works published in the last 20 years allows us to conclude that the mechanisms of various drugs' anti-cephalalgic action, 20,23 as well as the involvement of different neurotransmitter systems in the pathogenesis of migraine 19,27 were predominantly explored in the non-sensitised model of trigeminodurovascular nociception, leading to the impression that the predictive value of this model is higher than that of the sensitisation model.…”

Newer Research and its Significance

“…62 Administration of nitric oxide donors has been found to increase firing rates within the rat spinal trigeminal nucleus, and pretreatment with CGRP receptor antagonists can blunt this increased neuronal activity. 63,64 Another study 65 reported release of CGRP in the dura mater, after application of nitric oxide donors, promoting increases in meningeal blood flow. Therefore, nitric oxide has been postulated to be one of the molecules released during the cascade of neuronal events in the course of a migraine attack.…”