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László Vécsei - One of the best experts on this subject based on the ideXlab platform.

  • Effect of dural inflammatory soup application on activation and sensitization markers in the Caudal Trigeminal Nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid.
    The journal of headache and pain, 2021
    Co-Authors: Eleonóra Spekker, Klaudia Flóra Laborc, Zsuzsanna Bohár, Mónika Szűcs, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Árpád Párdutz
    Abstract:

    The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the Trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in Trigeminal activation. We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the Caudal Trigeminal Nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the Caudal Trigeminal Nucleus was removed for immunohistochemistry. Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the Caudal Trigeminal Nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.

  • Effect of dural inflammatory soup application on activation and sensitization markers in the Caudal Trigeminal Nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid
    The Journal of Headache and Pain, 2021
    Co-Authors: Eleonóra Spekker, Klaudia Flóra Laborc, Zsuzsanna Bohár, Mónika Szűcs, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Árpád Párdutz
    Abstract:

    Abstract Background The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the Trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in Trigeminal activation. Aim We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the Caudal Trigeminal Nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. Material and methods After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the Caudal Trigeminal Nucleus was removed for immunohistochemistry. Results and conclusion Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the Caudal Trigeminal Nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.

  • Trigeminal activation patterns evoked by chemical stimulation of the dura mater in rats
    The Journal of Headache and Pain, 2020
    Co-Authors: Klaudia Flóra Laborc, Eleonóra Spekker, Zsuzsanna Bohár, Mónika Szűcs, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Árpád Párdutz
    Abstract:

    Although migraine is one of the most common primary headaches, its therapy is still limited in many cases. The use of animal models is crucial in the development of novel therapeutic strategies, but unfortunately, none of them show all aspects of the disease, therefore, there is a constant need for further improvement in this field. The application of inflammatory agents on the dura mater is a widely accepted method to mimic neurogenic inflammation in rodents, which plays a key role in the pathomechanism of migraine. Complete Freund’s Adjuvant (CFA), and a mixture of inflammatory mediators, called inflammatory soup (IS) are often used for this purpose. To examine the activation pattern that is caused by chemical stimulation of dura mater, we applied CFA or IS over the right parietal lobe. After 2 h and 4 h (CFA groups), or 2.5 h and 4 h (IS groups), animals were perfused, and c-Fos immunoreactive cells were counted in the Caudal Trigeminal Nucleus. To explore every pitfall, we examined whether our surgical procedure (anesthetic drug, stereotaxic apparatus, local lidocaine) can alter the results under the same experimental settings. c-Fos labeled cells were counted in the second-order neuron area based on the somatotopic organization of the Trigeminal nerve branches. We could not find any difference between the CFA and physiological saline group neither 2 h, nor 4 h after dural stimulation. IS caused significant difference after both time points between IS treated and control group, and between treated (right) and control (left) side. Stereotaxic frame usage had a substantial effect on the obtained results. Counting c-Fos immunoreactive cells based on somatotopic organization of the Trigeminal nerve helped to examine the effect of chemical stimulation of dura in a more specific way. As a result, the use of IS over the parietal lobe caused activation in the area of the ophthalmic nerve. To see this effect, the use of lidocaine anesthesia is indispensable. In conclusion, application of IS on the dura mater induces short-term, more robust c-Fos activation than CFA, therefore it might offer a better approach to model acute migraine headache in rodents.

  • Diverse effects of Brilliant Blue G administration in models of Trigeminal activation in the rat
    Journal of Neural Transmission, 2015
    Co-Authors: Zsuzsanna Bohár, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Lilla Tar, Anna M. László, Alexandra Büki, Nikolett Szabadi, Veronika Vraukó, Árpád Párdutz
    Abstract:

    Activation of the Trigeminal system plays an important role in the pathomechanism of headaches. A better understanding of Trigeminal pain processing is expected to provide information helping to unravel the background of these diseases. ATP, a key modulator of nociceptive processing, acts on ligand-gated P2X receptors. Antagonists of the P2X7 receptors, such as Brilliant Blue G (BBG), have proved effective in several models of pain. We have investigated the effects of BBG after electrical stimulation of the Trigeminal ganglion and in the orofacial formalin test in the rat. The right Trigeminal ganglion of male rats was stimulated either with 5 Hz, 0.5 mA pulses for 5 min (mild procedure) or with 10 Hz, 0.5 mA pulses for 30 min (robust procedure), preceded by 50 mg/kg i.v. BBG. The animals were processed for c-Fos and calcitonin gene-related peptide (CGRP) immunohistochemistry. In the orofacial formalin test, 50 μL of 1.5 % formalin was injected into the right whisker pad of awake rats, following the pre-treatment with BBG. Behaviour was monitored for 45 min, and c-Fos and CGRP immunohistochemistry was performed. BBG attenuated the increase in c-Fos-positive cells in the Caudal Trigeminal Nucleus (TNC) after robust stimulation, but not after mild stimulation. No alterations in CGRP levels were found with either methodology. BBG did not mitigate either the behaviour or the increase in c-Fos-positive cells in the TNC during the orofacial formalin test. These results indicate that P2X7 receptors may have a role in the modulation of nociception in the Trigeminal system.

  • Kynurenate derivative attenuates the nitroglycerin-induced CamKIIα and CGRP expression changes.
    Headache, 2009
    Co-Authors: Enikő Vamos, Árpád Párdutz, Annamária Fejes, János Tajti, József Toldi, Ferenc Fulop, Júlia Koch, László Vécsei
    Abstract:

    (Headache 2010;50:834-843) Objective.— To examine the efficacy of L-kynurenine and a novel kynurenic acid derivative on the nitroglycerin-induced calmodulin-dependent protein kinase II alpha (CamKIIα) and calcitonin gene-related peptide (CGRP) expression changes in the rat Caudal Trigeminal Nucleus. Background.— Systemic administration of the nitric oxide donor nitroglycerin can trigger an attack in migraineurs. In the rat, nitroglycerin activates second-order neurons in the Caudal Trigeminal Nucleus, and increases expression of the CamKIIα and decreases that of the CGRP there. As glutamatergic mechanisms may be crucial in Trigeminal pain processing, the aim of our study was to examine the effects of L-kynurenine, a metabolic precursor of the N-methyl D-aspartate receptor antagonist kynurenic acid, on the nitroglycerin-induced changes in CamKIIα and CGRP immunoreactivity. Methods.— One hour before the nitroglycerin (10 mg/kg bodyweight, s.c.) injection, the animals were pretreated with L-kynurenine (300 mg/kg bodyweight, i.p.) or 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride (300 mg/kg bodyweight, i.p.), a novel kynurenic acid derivative. Four hours later, the rats were perfused transcardially and the cervical spinal cord segments were removed for immunohistochemistry. Results.— L-kynurenine and 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride pretreatment attenuated the nitroglycerin-induced changes in CamKIIα and CGRP immunoreactivity in the rat Caudal Trigeminal Nucleus. Conclusions.— These findings suggest a mechanism by which the inhibition of the excitatory amino acid receptors by kynurenic acid and its derivatives can alter Trigeminal nociception.

Árpád Párdutz - One of the best experts on this subject based on the ideXlab platform.

  • Effect of dural inflammatory soup application on activation and sensitization markers in the Caudal Trigeminal Nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid.
    The journal of headache and pain, 2021
    Co-Authors: Eleonóra Spekker, Klaudia Flóra Laborc, Zsuzsanna Bohár, Mónika Szűcs, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Árpád Párdutz
    Abstract:

    The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the Trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in Trigeminal activation. We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the Caudal Trigeminal Nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the Caudal Trigeminal Nucleus was removed for immunohistochemistry. Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the Caudal Trigeminal Nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.

  • Effect of dural inflammatory soup application on activation and sensitization markers in the Caudal Trigeminal Nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid
    The Journal of Headache and Pain, 2021
    Co-Authors: Eleonóra Spekker, Klaudia Flóra Laborc, Zsuzsanna Bohár, Mónika Szűcs, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Árpád Párdutz
    Abstract:

    Abstract Background The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the Trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in Trigeminal activation. Aim We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the Caudal Trigeminal Nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. Material and methods After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the Caudal Trigeminal Nucleus was removed for immunohistochemistry. Results and conclusion Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the Caudal Trigeminal Nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.

  • Trigeminal activation patterns evoked by chemical stimulation of the dura mater in rats
    The Journal of Headache and Pain, 2020
    Co-Authors: Klaudia Flóra Laborc, Eleonóra Spekker, Zsuzsanna Bohár, Mónika Szűcs, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Árpád Párdutz
    Abstract:

    Although migraine is one of the most common primary headaches, its therapy is still limited in many cases. The use of animal models is crucial in the development of novel therapeutic strategies, but unfortunately, none of them show all aspects of the disease, therefore, there is a constant need for further improvement in this field. The application of inflammatory agents on the dura mater is a widely accepted method to mimic neurogenic inflammation in rodents, which plays a key role in the pathomechanism of migraine. Complete Freund’s Adjuvant (CFA), and a mixture of inflammatory mediators, called inflammatory soup (IS) are often used for this purpose. To examine the activation pattern that is caused by chemical stimulation of dura mater, we applied CFA or IS over the right parietal lobe. After 2 h and 4 h (CFA groups), or 2.5 h and 4 h (IS groups), animals were perfused, and c-Fos immunoreactive cells were counted in the Caudal Trigeminal Nucleus. To explore every pitfall, we examined whether our surgical procedure (anesthetic drug, stereotaxic apparatus, local lidocaine) can alter the results under the same experimental settings. c-Fos labeled cells were counted in the second-order neuron area based on the somatotopic organization of the Trigeminal nerve branches. We could not find any difference between the CFA and physiological saline group neither 2 h, nor 4 h after dural stimulation. IS caused significant difference after both time points between IS treated and control group, and between treated (right) and control (left) side. Stereotaxic frame usage had a substantial effect on the obtained results. Counting c-Fos immunoreactive cells based on somatotopic organization of the Trigeminal nerve helped to examine the effect of chemical stimulation of dura in a more specific way. As a result, the use of IS over the parietal lobe caused activation in the area of the ophthalmic nerve. To see this effect, the use of lidocaine anesthesia is indispensable. In conclusion, application of IS on the dura mater induces short-term, more robust c-Fos activation than CFA, therefore it might offer a better approach to model acute migraine headache in rodents.

  • Diverse effects of Brilliant Blue G administration in models of Trigeminal activation in the rat
    Journal of Neural Transmission, 2015
    Co-Authors: Zsuzsanna Bohár, Gábor Nagy-grócz, Annamária Fejes-szabó, László Vécsei, Lilla Tar, Anna M. László, Alexandra Büki, Nikolett Szabadi, Veronika Vraukó, Árpád Párdutz
    Abstract:

    Activation of the Trigeminal system plays an important role in the pathomechanism of headaches. A better understanding of Trigeminal pain processing is expected to provide information helping to unravel the background of these diseases. ATP, a key modulator of nociceptive processing, acts on ligand-gated P2X receptors. Antagonists of the P2X7 receptors, such as Brilliant Blue G (BBG), have proved effective in several models of pain. We have investigated the effects of BBG after electrical stimulation of the Trigeminal ganglion and in the orofacial formalin test in the rat. The right Trigeminal ganglion of male rats was stimulated either with 5 Hz, 0.5 mA pulses for 5 min (mild procedure) or with 10 Hz, 0.5 mA pulses for 30 min (robust procedure), preceded by 50 mg/kg i.v. BBG. The animals were processed for c-Fos and calcitonin gene-related peptide (CGRP) immunohistochemistry. In the orofacial formalin test, 50 μL of 1.5 % formalin was injected into the right whisker pad of awake rats, following the pre-treatment with BBG. Behaviour was monitored for 45 min, and c-Fos and CGRP immunohistochemistry was performed. BBG attenuated the increase in c-Fos-positive cells in the Caudal Trigeminal Nucleus (TNC) after robust stimulation, but not after mild stimulation. No alterations in CGRP levels were found with either methodology. BBG did not mitigate either the behaviour or the increase in c-Fos-positive cells in the TNC during the orofacial formalin test. These results indicate that P2X7 receptors may have a role in the modulation of nociception in the Trigeminal system.

  • Kynurenate derivative attenuates the nitroglycerin-induced CamKIIα and CGRP expression changes.
    Headache, 2009
    Co-Authors: Enikő Vamos, Árpád Párdutz, Annamária Fejes, János Tajti, József Toldi, Ferenc Fulop, Júlia Koch, László Vécsei
    Abstract:

    (Headache 2010;50:834-843) Objective.— To examine the efficacy of L-kynurenine and a novel kynurenic acid derivative on the nitroglycerin-induced calmodulin-dependent protein kinase II alpha (CamKIIα) and calcitonin gene-related peptide (CGRP) expression changes in the rat Caudal Trigeminal Nucleus. Background.— Systemic administration of the nitric oxide donor nitroglycerin can trigger an attack in migraineurs. In the rat, nitroglycerin activates second-order neurons in the Caudal Trigeminal Nucleus, and increases expression of the CamKIIα and decreases that of the CGRP there. As glutamatergic mechanisms may be crucial in Trigeminal pain processing, the aim of our study was to examine the effects of L-kynurenine, a metabolic precursor of the N-methyl D-aspartate receptor antagonist kynurenic acid, on the nitroglycerin-induced changes in CamKIIα and CGRP immunoreactivity. Methods.— One hour before the nitroglycerin (10 mg/kg bodyweight, s.c.) injection, the animals were pretreated with L-kynurenine (300 mg/kg bodyweight, i.p.) or 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride (300 mg/kg bodyweight, i.p.), a novel kynurenic acid derivative. Four hours later, the rats were perfused transcardially and the cervical spinal cord segments were removed for immunohistochemistry. Results.— L-kynurenine and 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride pretreatment attenuated the nitroglycerin-induced changes in CamKIIα and CGRP immunoreactivity in the rat Caudal Trigeminal Nucleus. Conclusions.— These findings suggest a mechanism by which the inhibition of the excitatory amino acid receptors by kynurenic acid and its derivatives can alter Trigeminal nociception.

A T Mcknight - One of the best experts on this subject based on the ideXlab platform.

  • reduction by gabapentin of k evoked release of 3h glutamate from the Caudal Trigeminal Nucleus of the streptozotocin treated rat
    British Journal of Pharmacology, 2004
    Co-Authors: Yannick P Maneuf, R Blake, Nick Andrews, A T Mcknight
    Abstract:

    Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K(+)-evoked glutamate release in rat Trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the Trigeminal slice from the streptozotocin (STZ)-treated rat. 1. At 4 weeks following STZ treatment (50 mg kg(-1) i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P<0.001) of tactile allodynia (assessed using von Frey filaments) that did not appear to correlate with blood glucose levels. 2. In this study, we demonstrated that, after STZ treatment, 30 microM gabapentin reduced K(+)-evoked release of [(3)H]-glutamate in either normal (11 mM) or high (30 mM) glucose conditions by 24 and 22%, respectively. In the normal rat, gabapentin (up to 100 microM) is ordinarily unable to affect release of glutamate from the Trigeminal slice. 3. The uptake of glutamate in Sp5C punches from streptozotocin-treated rats was reduced under normal glucose conditions (41.7% of control), whereas high glucose restored uptake to normal (84.7% of control). 4. The addition of 1 microm substance P potentiated the evoked release of glutamate in both normal (40% increase) and high glucose (28%), and this was blocked by gabapentin (30 microM) in both conditions. It is interesting to speculate that this ability of gabapentin to reduce the release of glutamate in the Trigeminal Nucleus after streptozotocin treatment may be of relevance to the antihyperalgesic-allodynic actions of the drug.

  • Reduction by gabapentin of K+-evoked release of [3H]-glutamate from the Caudal Trigeminal Nucleus of the streptozotocin-treated rat
    British journal of pharmacology, 2004
    Co-Authors: Yannick P Maneuf, R Blake, Nick Andrews, A T Mcknight
    Abstract:

    Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K(+)-evoked glutamate release in rat Trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the Trigeminal slice from the streptozotocin (STZ)-treated rat. 1. At 4 weeks following STZ treatment (50 mg kg(-1) i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P

  • gabapentin inhibits the substance p facilitated k evoked release of 3h glutamate from rat Caudal Trigeminal Nucleus slices
    Pain, 2001
    Co-Authors: Yannick P Maneuf, John Hughes, A T Mcknight
    Abstract:

    Abstract The effect of gabapentin on the release of the spinal sensory neurotransmitter glutamate has been investigated in an in vitro model using a perfused thin slice preparation from the rat brainstem containing the spinal Trigeminal Caudal subNucleus (Sp5C) and pre-incubated with [3H]glutamate. Addition of excess K+ to the perfusing solution increased the content of tritium in the perfusate. The prior addition of substance P increased this index of glutamate release in a concentration-dependent manner, with the mean maximum of around 50% increase obtained at 1–3 μM. The action of substance P to increase the evoked release of glutamate was blocked by the antagonist CP-99994, suggesting a specific involvement of the NK1 receptor in mediating the facilitatory effect. On its own, gabapentin at up to 100 μM did not modify the baseline level of K+-evoked release of glutamate; however, gabapentin caused a concentration-dependent decrease of the facilitatory effect of substance P (EC50=6.49 μM). The R-(−)- and S-(+)-isomers of 3-isobutylgaba were then tested against the increase in K+-evoked release of glutamate by substance P. S-(+)-3-isobutylgaba (pregabalin) at 30 μM acted like gabapentin to reduce the substance P-mediated increase of release almost to the baseline level of K+-evoked release, while in contrast the R-(−)-isomer at this concentration produced no reduction, and rather a trend towards a further enhancement of the potentiating effect of substance P. In conclusion, we have found and characterized an effect of gabapentin that is of possible mechanistic relevance to the anti-hyperalgesic/allodynic actions of this compound.

  • Block by gabapentin of the facilitation of glutamate release from rat Trigeminal Nucleus following activation of protein kinase C or adenylyl cyclase
    British journal of pharmacology, 2001
    Co-Authors: Yannick P Maneuf, A T Mcknight
    Abstract:

    The effect of activation of protein kinase C (PKC) or adenylyl cyclase on release of glutamate has been investigated in a perfused slice preparation from the rat Caudal Trigeminal Nucleus. Stimulation of PKC by phorbol 12-myristate 13-acetate (PMA) produced a concentration-dependent increase in K+-evoked release of [2H]-glutamate (maximum increase 45%, EC50 11.8 nM), but in the presence of gabapentin (30 μM) the facilitation of release was blocked. The adenylyl cyclase activator forskolin (FSK) also induced a concentration-dependent increase in K+-evoked release of [3H]-glutamate (maximum increase 36%, EC50 2.4 μM), and again this facilitatory effect was blocked by gabapentin (30 μM). We suggest that these results may be of relevance to the antihyperalgesic properties of gabapentin, in conditions where concomitant release of substance P and CGRP produces activation of PKC and adenylyl cyclase respectively. British Journal of Pharmacology (2001) 134, 237–240; doi:10.1038/sj.bjp.0704227

József Toldi - One of the best experts on this subject based on the ideXlab platform.

  • Kynurenate derivative attenuates the nitroglycerin-induced CamKIIα and CGRP expression changes.
    Headache, 2009
    Co-Authors: Enikő Vamos, Árpád Párdutz, Annamária Fejes, János Tajti, József Toldi, Ferenc Fulop, Júlia Koch, László Vécsei
    Abstract:

    (Headache 2010;50:834-843) Objective.— To examine the efficacy of L-kynurenine and a novel kynurenic acid derivative on the nitroglycerin-induced calmodulin-dependent protein kinase II alpha (CamKIIα) and calcitonin gene-related peptide (CGRP) expression changes in the rat Caudal Trigeminal Nucleus. Background.— Systemic administration of the nitric oxide donor nitroglycerin can trigger an attack in migraineurs. In the rat, nitroglycerin activates second-order neurons in the Caudal Trigeminal Nucleus, and increases expression of the CamKIIα and decreases that of the CGRP there. As glutamatergic mechanisms may be crucial in Trigeminal pain processing, the aim of our study was to examine the effects of L-kynurenine, a metabolic precursor of the N-methyl D-aspartate receptor antagonist kynurenic acid, on the nitroglycerin-induced changes in CamKIIα and CGRP immunoreactivity. Methods.— One hour before the nitroglycerin (10 mg/kg bodyweight, s.c.) injection, the animals were pretreated with L-kynurenine (300 mg/kg bodyweight, i.p.) or 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride (300 mg/kg bodyweight, i.p.), a novel kynurenic acid derivative. Four hours later, the rats were perfused transcardially and the cervical spinal cord segments were removed for immunohistochemistry. Results.— L-kynurenine and 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride pretreatment attenuated the nitroglycerin-induced changes in CamKIIα and CGRP immunoreactivity in the rat Caudal Trigeminal Nucleus. Conclusions.— These findings suggest a mechanism by which the inhibition of the excitatory amino acid receptors by kynurenic acid and its derivatives can alter Trigeminal nociception.

  • Modulatory effects of probenecid on the nitroglycerin-induced changes in the rat Caudal Trigeminal Nucleus.
    European Journal of Pharmacology, 2009
    Co-Authors: Eniko Vamos, Árpád Párdutz, Annamária Fejes, János Tajti, József Toldi, László Vécsei
    Abstract:

    Four hours after systemic administration of the nitric oxide donor nitroglycerin (10 mg/kg bodyweight, s.c.), the neurons of the rat Caudal Trigeminal Nucleus are activated, the area covered by calcitonin gene-related peptide (CGRP)-immunoreactive fibres is decreased and the neuronal nitric oxide synthase (nNOS)- and the calmodulin-dependent protein kinase II alpha (CamKIIα)-immunopositive neurons in the same area are increased. Probenecid is a non-selective inhibitor of multidrug-resistance associated proteins and organic anion transporters thus it can modulate the transport functions in the central nervous system influencing nociception. Accordingly, the aim of the present experiments was to examine the effects of probenecid administration on the nitroglycerin-induced expressions of nNOS, CamKIIα and CGRP in the rat Caudal Trigeminal Nucleus. Probenecid (200 mg/kg bodyweight, i.p.) pretreatment proved to mitigate the nitroglycerin-induced changes in expression in the rat Caudal Trigeminal Nucleus. The data suggest that the changes caused by nitroglycerin in the expressions of CGRP, nNOS and CamKIIα can be influenced by probenecid modulating the inflammatory functions in the nervous system. These data may be of relevance for the pathogenesis of migraine headache.

  • l kynurenine combined with probenecid and the novel synthetic kynurenic acid derivative attenuate nitroglycerin induced nnos in the rat Caudal Trigeminal Nucleus
    Neuropharmacology, 2009
    Co-Authors: Enikő Vamos, Zsuzsanna Bohár, Árpád Párdutz, János Tajti, József Toldi, Hedvig Varga, Ferenc Fulop, László Vécsei
    Abstract:

    Abstract Systemic administration of the nitric oxide (NO) donor nitroglycerin (NTG) triggers a delayed attack without aura in many migraineurs, but not in healthy volunteers. In rats, 4 h after the systemic administration of NTG (10 mg/kg bw, s.c.), the neurons of the Caudal Trigeminal Nucleus (TNC) are activated and the expression of neuronal NO synthase (nNOS) in the same area is increased suggesting a self-amplifying process in the Trigeminal system, which seems to be crucial in migraine pathogenesis. Kynurenic acid (KYNA) and its analogues may exert modulatory effects in many neuropathological conditions, probably via N-methyl- d -aspartate (NMDA) antagonism. Since NMDA receptors play a crucial role in Trigeminal pain processing, the aim of our experiments was to compare the effects of l -kynurenine ( l -KYN) combined with probenecid (PROB) or with 2-(2- N , N -dimethylaminoethylamine-1-carbonyl)-1 H -quinolin-4-one hydrochloride alone, a newly synthetized KYNA derivative, on the NTG-induced nNOS expression in the rat TNC. Pretreatment with l -KYN (300 mg/kg bw, i.p.) together with PROB (200 mg/kg bw, i.p.) and KYNA derivative (300 mg/kg bw, i.p.) attenuated the NTG-induced nNOS expression in the rat TNC. Our data suggest that the stimulating effect of NTG, and thus of NO, on the expression of nNOS might be modulated by increasing the KYNA level in the brain, probably through the NMDA receptors. These data could help promote a better understanding of the pathogenesis of headaches and the action of antimigraine drugs.

  • the kynurenate analog szr 72 prevents the nitroglycerol induced increase of c fos immunoreactivity in the rat Caudal Trigeminal Nucleus comparative studies of the effects of szr 72 and kynurenic acid
    Neuroscience Research, 2008
    Co-Authors: Elizabeth Knyiharcsillik, József Toldi, A. Mihály, Beata Krisztinpeva, Hermina Robotka, Istvan Szatmari, Ferenc Fulop, B Csillik, László Vécsei
    Abstract:

    Administration of nitroglycerol in a migraine model results in an increased number of c-fos-expressing secondary sensory neurons in the Caudal Trigeminal Nucleus. Since synapses between first- and second-order Trigeminal neurons are mediated by excitatory amino acids, NMDA receptors are inhibited by kynurenic acid, though this crosses the blood-brain barrier only poorly. Systemic treatment of rats with SZR-72, a newly synthetized kynurenic acid analog, diminished the nitroglycerol-induced increase of c-fos immunoreactivity in the brain stem highly significantly, while treatment with kynurenic acid resulted in a significantly smaller decrease, proving that SZR-72 is much more effective than kynurenic acid.

  • Prevention of electrical stimulation-induced increase of c-fos immunoreaction in the Caudal Trigeminal Nucleus by kynurenine combined with probenecid.
    Neuroscience letters, 2007
    Co-Authors: Elizabeth Knyihár-csillik, József Toldi, B. Krisztin-péva, Z. Chadaide, H. Németh, Robert Fenyo, László Vécsei
    Abstract:

    The systemic administration of nitroglycerine, regarded as a migraine model, was previously observed to result in an increased number of c-fos immunoreactive secondary sensory neurons in the Caudal Trigeminal Nucleus, which forward nociceptive impulses to the thalamus. The present investigation tested the hypothesis of whether kynurenine in combination with systemically administered probenecid protects second-order Trigeminal neurons against stimulation arriving via central processes of Trigeminal ganglion cells. Electrical stimulation of the Trigeminal ganglion, one of the experimental migraine models, is known to induce an increase in the number of c-fos immunoreactive second-order nerve cells projecting to the thalamus. Since the synapses between first- and second-order Trigeminal neurons are presumed to be mediated by excitatory amino acids, postsynaptic NMDA receptors should be inhibited by kynurenic acid, an endogenous NMDA receptor antagonist. Kynurenic acid, however, does not cross the blood-brain barrier, and its use as a neuroprotective agent is therefore not feasible. In contrast, kynurenine, from which kynurenic acid is formed on the action of kynurenine aminotransferase, passes the blood-brain barrier without difficulty. After the i.p. injection of kynurenine combined with probenecid it was found that the stimulation-induced increase in the c-fos immunoreactivity of the secondary sensory neurons does not occur.

Yannick P Maneuf - One of the best experts on this subject based on the ideXlab platform.

  • reduction by gabapentin of k evoked release of 3h glutamate from the Caudal Trigeminal Nucleus of the streptozotocin treated rat
    British Journal of Pharmacology, 2004
    Co-Authors: Yannick P Maneuf, R Blake, Nick Andrews, A T Mcknight
    Abstract:

    Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K(+)-evoked glutamate release in rat Trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the Trigeminal slice from the streptozotocin (STZ)-treated rat. 1. At 4 weeks following STZ treatment (50 mg kg(-1) i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P<0.001) of tactile allodynia (assessed using von Frey filaments) that did not appear to correlate with blood glucose levels. 2. In this study, we demonstrated that, after STZ treatment, 30 microM gabapentin reduced K(+)-evoked release of [(3)H]-glutamate in either normal (11 mM) or high (30 mM) glucose conditions by 24 and 22%, respectively. In the normal rat, gabapentin (up to 100 microM) is ordinarily unable to affect release of glutamate from the Trigeminal slice. 3. The uptake of glutamate in Sp5C punches from streptozotocin-treated rats was reduced under normal glucose conditions (41.7% of control), whereas high glucose restored uptake to normal (84.7% of control). 4. The addition of 1 microm substance P potentiated the evoked release of glutamate in both normal (40% increase) and high glucose (28%), and this was blocked by gabapentin (30 microM) in both conditions. It is interesting to speculate that this ability of gabapentin to reduce the release of glutamate in the Trigeminal Nucleus after streptozotocin treatment may be of relevance to the antihyperalgesic-allodynic actions of the drug.

  • Reduction by gabapentin of K+-evoked release of [3H]-glutamate from the Caudal Trigeminal Nucleus of the streptozotocin-treated rat
    British journal of pharmacology, 2004
    Co-Authors: Yannick P Maneuf, R Blake, Nick Andrews, A T Mcknight
    Abstract:

    Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K(+)-evoked glutamate release in rat Trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the Trigeminal slice from the streptozotocin (STZ)-treated rat. 1. At 4 weeks following STZ treatment (50 mg kg(-1) i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P

  • gabapentin inhibits the substance p facilitated k evoked release of 3h glutamate from rat Caudal Trigeminal Nucleus slices
    Pain, 2001
    Co-Authors: Yannick P Maneuf, John Hughes, A T Mcknight
    Abstract:

    Abstract The effect of gabapentin on the release of the spinal sensory neurotransmitter glutamate has been investigated in an in vitro model using a perfused thin slice preparation from the rat brainstem containing the spinal Trigeminal Caudal subNucleus (Sp5C) and pre-incubated with [3H]glutamate. Addition of excess K+ to the perfusing solution increased the content of tritium in the perfusate. The prior addition of substance P increased this index of glutamate release in a concentration-dependent manner, with the mean maximum of around 50% increase obtained at 1–3 μM. The action of substance P to increase the evoked release of glutamate was blocked by the antagonist CP-99994, suggesting a specific involvement of the NK1 receptor in mediating the facilitatory effect. On its own, gabapentin at up to 100 μM did not modify the baseline level of K+-evoked release of glutamate; however, gabapentin caused a concentration-dependent decrease of the facilitatory effect of substance P (EC50=6.49 μM). The R-(−)- and S-(+)-isomers of 3-isobutylgaba were then tested against the increase in K+-evoked release of glutamate by substance P. S-(+)-3-isobutylgaba (pregabalin) at 30 μM acted like gabapentin to reduce the substance P-mediated increase of release almost to the baseline level of K+-evoked release, while in contrast the R-(−)-isomer at this concentration produced no reduction, and rather a trend towards a further enhancement of the potentiating effect of substance P. In conclusion, we have found and characterized an effect of gabapentin that is of possible mechanistic relevance to the anti-hyperalgesic/allodynic actions of this compound.

  • Block by gabapentin of the facilitation of glutamate release from rat Trigeminal Nucleus following activation of protein kinase C or adenylyl cyclase
    British journal of pharmacology, 2001
    Co-Authors: Yannick P Maneuf, A T Mcknight
    Abstract:

    The effect of activation of protein kinase C (PKC) or adenylyl cyclase on release of glutamate has been investigated in a perfused slice preparation from the rat Caudal Trigeminal Nucleus. Stimulation of PKC by phorbol 12-myristate 13-acetate (PMA) produced a concentration-dependent increase in K+-evoked release of [2H]-glutamate (maximum increase 45%, EC50 11.8 nM), but in the presence of gabapentin (30 μM) the facilitation of release was blocked. The adenylyl cyclase activator forskolin (FSK) also induced a concentration-dependent increase in K+-evoked release of [3H]-glutamate (maximum increase 36%, EC50 2.4 μM), and again this facilitatory effect was blocked by gabapentin (30 μM). We suggest that these results may be of relevance to the antihyperalgesic properties of gabapentin, in conditions where concomitant release of substance P and CGRP produces activation of PKC and adenylyl cyclase respectively. British Journal of Pharmacology (2001) 134, 237–240; doi:10.1038/sj.bjp.0704227