Activity Of Spinal Trigeminal Neurons Research Articles

Nitroxyl Delivered by Angeli's Salt Causes Short-Lasting Activation Followed by Long-Lasting Deactivation of Meningeal Afferents in Models of Headache Generation.

The role of TRPA1 receptor channels in meningeal nociception underlying the generation of headaches is still unclear. Activating as well as inhibitory effects of TRPA1 agonists have been reported in animal models of headache. The aim of the present study was to clarify the effect of the TRPA1 agonist nitroxyl (HNO) delivered by Angeli’s salt in two rodent models of meningeal nociception. Single fibre recordings were performed using half-skull preparations of mice (C57BL/6) in vitro. Angeli’s salt solution (AS, 300 µM) caused short-lasting vigorous increases in neuronal activity of primary meningeal afferents, followed by deactivation and desensitisation. These effects were similar in TRPA1 knockout and even more pronounced in TRPA1/TRPV1 double-knockout mice in comparison to wild-type mice. The activity of spinal trigeminal neurons with afferent input from the dura mater was recorded in vivo in anesthetised rats. AS (300 µM) or the TRPA1 agonist acrolein (100 and 300 µM) was applied to the exposed dura mater. AS caused no significant changes in spontaneous activity, while the mechanically evoked activity was reduced after acrolein application. These results do not confirm the assumption that activation of trigeminal TRPA1 receptor channels triggers the generation of headaches or contributes to its aggravation. Instead, there is evidence that TRPA1 activation may have an inhibitory function in the nociceptive trigeminal system.

Effect of a calcitonin gene-related peptide-binding L-RNA aptamer on neuronal activity in the rat spinal trigeminal nucleus

BackgroundCalcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine. In parallel, CGRP receptor inhibition has been shown to lower spinal trigeminal neuron activity in animal models of meningeal nociception.MethodsIn a rat model of meningeal nociception, single cell activity of neurons in the spinal trigeminal nucleus with meningeal afferent input was recorded to test a further pharmacological approach, scavenging CGRP with a CGRP-binding l-RNA oligonucleotide, the l-aptamer NOX-C89. Cumulative ascending doses of NOX-C89 were intravenously infused.ResultsSpontaneous activity of spinal trigeminal neurons did not change after 0.05 mg/kg NOX-C89, however, after additional infusion of 0.5 mg/kg and 5 mg/kg NOX-C89, spontaneous activity was dose-dependently reduced. Identical doses of a control l-aptamer had no effect. This pharmacological effect of NOX-C89 was observed 10–25 min after infusion, but no difference was detected in the period 0–5 min. For comparison, the previously investigated CGRP receptor antagonist olcegepant had reduced activity within 5 min after infusion. Alongside the reduced spontaneous activity, after infusion of NOX-C89 the heat-induced neuronal activity was abolished.ConclusionsScavenging CGRP by mirror-image RNA aptamers provides further evidence that this approach can be used to control spinal trigeminal activity.

Hydrogen Sulfide Mediating both Excitatory and Inhibitory Effects in a Rat Model of Meningeal Nociception and Headache Generation.

Hydrogen sulfide (H2S) is a neuromodulator acting through nitroxyl (HNO) when it reacts with nitric oxide (NO). HNO activates transient receptor potential channels of the ankyrin type 1 (TRPA1) causing release of calcitonin gene-related peptide from primary afferents. Activation of meningeal nociceptors projecting to the human spinal trigeminal nucleus (STN) may lead to headaches. In a rat model of meningeal nociception, the activity of spinal trigeminal neurons was used as read-out for the interaction between H2S and NO. In anesthetized rats extracellular recordings from single neurons in the STN were made. Sodium sulfide (Na2S) producing H2S in the tissue and the NO donor diethylamine-NONOate (DEA-NONOate) were infused intravenously. H2S was also locally applied onto the exposed cranial dura mater or the medulla. Endogenous production of H2S was inhibited by oxamic acid, and NO production was inhibited by nitro-l-arginine methyl ester hydrochloride (l-NAME) to manipulate endogenous HNO formation. Systemic administration of Na2S was followed either by increased ongoing activity (in 73%) or decreased activity (in 27% of units). Topical application of Na2S onto the cranial dura mater caused a short-lasting activation followed by a long-lasting decrease in activity in the majority of units (70%). Systemic administration of DEA-NONOate increased neuronal activity, subsequent infusion of Na2S added to this effect, whereas DEA-NONOate did not augment the activity after Na2S. The stimulating effect of DEA-NONOate was inhibited by oxamic acid in 75% of units, and l-NAME following Na2S administration returned the activity to baseline. Individual spinal trigeminal neurons may be activated or (less frequently) inhibited by the TRPA1 agonist HNO, presumably formed by H2S and NO in the STN, whereby endogenous H2S production seems to be rate-limiting. Activation of meningeal afferents by HNO may induce decreased spinal trigeminal activity, consistent with the elevation of the electrical threshold caused by TRPA1 activation in afferent fibers. Thus, the effects of H2S-NO-TRPA1 signaling depend on the site of action and the type of central neurons. The role of H2S-NO-TRPA1 in headache generation seems to be ambiguous.

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

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.

CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation

Calcitonin gene-related peptide (CGRP) and metabolic products of nitric oxide (NO) are increased in jugular venous plasma during migraine attacks and other primary headaches. Patients suffering from primary headaches are particularly sensitive to CGRP and NO donors responding with delayed headaches to an infusion of either of these substances. Accordingly, both CGRP and NO are considered as key mediators in migraine, and clinical trials have shown that inhibitors of CGRP receptors and NO synthase are effective in treating migraine. There is an implicit understanding that CGRP and NO systems interact, and here, we review the body of preclinical work on these systems focusing on the trigeminovascular system in migraine. NO derives from various cell types via 3 isoforms of NO synthase, whereas CGRP is produced from a subset of trigeminal afferents. In rodents, NO donors cause activity alterations on different levels of the trigeminal system including enhancement of CGRP release, which in turn results in arterial vasodilatation and possibly mast cell degranulation in the meninges. The activity of spinal trigeminal neurons, which is a sensitive integrative measure for trigeminal activity, is partly under the control of CGRP and NO. Both mediators facilitate nociceptive transmission, possibly via presynaptic mechanisms. These functions are supported by immunolocalization of CGRP receptor components on 3 trigeminovascular levels: cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus. Current data support a relationship of CGRP and NO actions on all levels of the trigeminovascular system and emphasize central CGRP receptors as possible therapeutic targets.

Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity

Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. α-CGRP (10(-5) M), the CGRP receptor antagonist olcegepant (10(-3) M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 μg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion.

Neuropeptide Effects in the Trigeminal System: Pathophysiology and Clinical Relevance in Migraine

The neuropeptides substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) have been considered as important mediators in migraine and other primary headaches. CGRP and VIP have been found at increased concentrations in jugular venous plasma during attacks of migraine or cluster headache, and CGRP receptor antagonists have recently been shown to be effective in migraine therapy. Substance P and CGRP are produced from a subset of trigeminal afferents, whereas VIP derives from parasympathetic efferents. Release of these neuropeptides in the meninges can cause arterial vasodilatation, mast cell degranulation and plasma extravasation in animal experiments, but only CGRP seems to be relevant in migraine. Animal models have confirmed the important role of CGRP in meningeal nociception. The activity of spinal trigeminal neurons is a sensitive integrative measure of trigeminal activity and is partly under the control of CGRP, most likely via central mechanisms. CGRP released from central terminals of trigeminal afferents in the spinal trigeminal nucleus seems to facilitate nociceptive transmission via presynaptic mechanisms. The central effect of CGRP is substantiated by suppression of nociceptive c-fos activation and neuronal activity in the spinal trigeminal nucleus following CGRP receptor inhibition. These proposed functions are supported by the localization of CGRP receptor components in the rat cranial dura mater, trigeminal ganglion and spinal trigeminal nucleus. The currently available data indicate multiple sites of CGRP action in trigeminal nociception and the pathogenesis of migraine; however, central CGRP receptors are likely to be the essential targets in the treatment of migraine using CGRP receptor antagonists.

Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus

Several lines of evidence suggest a major role of calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine and other primary headaches. Inhibition of CGRP receptors by olcegepant and telcagepant has been successfully used to treat acute migraine and to reduce the activity of spinal trigeminal neurons involved in meningeal nociception in rodents. The site of CGRP receptor inhibition is unclear, however. In adult Wistar rats anaesthetized with isofluorane systemic intravenous infusion (0.9 mg/kg) or unilateral facial injection (1 mM in 100 microl) of capsaicin was used to induce activity in the trigeminal nociceptive system. Animals were pre-treated either by saline or olcegepant. In comparison with vehicle infusion or the non-injected side of the face, capsaicin significantly increased the expression of the activation markers Fos in the spinal trigeminal nucleus and phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion. Pre-treatment with olcegepant (900 microg/kg) inhibited the capsaicin-induced expression of Fos throughout the spinal trigeminal nucleus by 57%. In contrast, the expression of phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion was not changed by olcegepant pre-treatment. CGRP receptor inhibition, which has been shown to decrease spinal trigeminal activity, is likely to occur in the central nervous system rather than in the periphery including the trigeminal ganglion. This may be important for future therapeutic interventions with CGRP receptor antagonists in migraine.

Ongoing activity in trigeminal wide-dynamic range neurons is driven from the periphery

Ongoing activity of spinal trigeminal neurons is observed under various conditions and suggested to be responsible for ongoing headache. It can be spontaneous, i.e. arising intrinsically from the neuron, or the product of descending influences from other central neurons, or maintained by ongoing afferent input. The aim of the present study was to examine if ongoing activity of neurons in different subnuclei of the spinal trigeminal nucleus is driven from peripheral afferent input. Experiments were performed in Wistar rats anesthetized with isoflurane or Nembutal/urethane. Ongoing activity of single wide-dynamic range (WDR) neurons was recorded with carbon fiber glass microelectrodes in two subnuclei of the spinal trigeminal nucleus: oral (Sp5O) and caudal (Sp5C). Peripheral receptive fields were evaluated using von Frey filaments. Sp5O neurons received peripheral input from facial areas innervated by the mandibular branch of the trigeminal nerve. Units in Sp5C had receptive fields in the surgically exposed dura mater and in facial areas innervated by the ophthalmic and maxillary branch of the trigeminal nerve. Saline or the local anesthetic lidocaine was locally applied onto the exposed dura mater or microinjected into V3 (for Sp5O units) or V1/V2 (for Sp5C units) divisions of the trigeminal ganglion via the infraorbital channel. Local application of lidocaine onto the exposed dura caused mechanical insensitivity of dural receptive fields but not significant decrease in ongoing activity. Microinjection of lidocaine but not saline into the trigeminal ganglion was followed by a substantial decrease in both the receptive field size and the activity of the recorded WDR units. Mechanical insensitivity of receptive fields after trigeminal ganglion blockade was accompanied by the disappearance of ongoing activity. We conclude that the ongoing activity of WDR neurons in the spinal trigeminal nucleus, which may be indicative for processes of sensitization, is driven remotely by ongoing afferent input.

Antiabsence drugs and inhibitory pathways.

Conditioning stimuli to the coronal gyrus or periventricular gray matter inhibit the activity of spinal trigeminal neurons. Valproate decreased the corticofugal inhibition of the spinal trigeminal nucleus, as did ethosuximide, trimethadione, and imipramine. Valproate and ethosuximide also decreased the periventricular inhibition of the spinal trigeminal nucleus, indicating that antiabsence drug depress subcortical inhibitory pathways as well as pathways of cortical origin. These results support the hypothesis that ability to depress inhibitory pathways is an important characteristic of antiabsence drugs. The effect of valproate and ethosuximide on periventricular inhibition also suggests that these anticonvulsants may act by preventing the spread of seizure activity through subcortical pathways.