Ildikó Papp

Publications of Ildikó Papp

• Plasticity of hyperpolarization-activated and cyclic nucleotid-gated cation channel subunit 2 expression in the spinal dorsal horn in inflammatory pain.

  Authors: Ildikó Papp, Krisztina Holló, Miklós Antal

  The European journal of neuroscience. 10/2010; 32(7):1193-201.

  A great deal of experimental evidence has already been accumulated that hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN) expressed by peripheral nerve fibers contributeA great deal of experimental evidence has already been accumulated that hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN) expressed by peripheral nerve fibers contribute to the initiation of nerve activities leading to pain. Complementing these findings, we have recently demonstrated that HCN subunit 2 (HCN2) channel protein is also widely expressed by axon terminals of substance P (SP)-containing peptidergic nociceptive primary afferents in laminae I-IIo of the spinal dorsal horn, and postulated that they may play a role in spinal pain processing. In the present study, we investigated how the expression of HCN2 ion channels in the spinal dorsal horn may change in inflammatory pain evoked by unilateral injection of complete Freund's adjuvant (CFA) into the hind paw of rats. We found that 3 days after CFA injection, when the nociceptive responsiveness of the inflamed hind paw had substantially increased, the numbers of HCN2-immunolabeled axon terminals were also significantly augmented in laminae I-IIo of the spinal dorsal horn ipsilateral to the site of CFA injection. The elevation of HCN2 immunoreactivity was paralleled by an increase in SP immunoreactivity. In addition, similarly to control animals, the co-localization between HCN2 and SP immunoreactivity was remarkably high, suggesting that central axon terminals of nociceptive primary afferents that increased their SP expression in response to CFA injection into the hind paw also increased their HCN2 expression. The results indicate that HCN2 ion channel mechanisms may play a role in SP-mediated spinal pain processing not only in naive animals but also in chronic inflammatory pain.

• Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn.

  Authors: Ildikó Papp, Péter Szucs, Krisztina Holló, Ferenc Erdélyi, Gábor Szabó, Miklós Antal

  The European journal of neuroscience. 10/2006; 24(5):1341-52.

  We have previously demonstrated that hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 (HCN2) is expressed by terminals of peptidergic nociceptive primary afferents inWe have previously demonstrated that hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 (HCN2) is expressed by terminals of peptidergic nociceptive primary afferents in laminae I-IIo of the rat spinal dorsal horn. In this study, we investigated the possible neurotransmitters and postsynaptic targets of these HCN2-expressing primary afferent terminals in the superficial spinal dorsal horn by using immunocytochemical methods. We demonstrated that HCN2 widely colocalizes with substance P (SP), and that HCN2-positive terminals that are also immunoreactive for SP form serial close appositions with dendrites and perikarya of neurokinin 1 receptor-immunoreactive neurons. It was also found that HCN2-immunoreactive terminals are frequently apposed to neurons that are immunoreactive for calbindin, micro-opioid receptor and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunit GluR2, markers for excitatory interneurons. Investigating HCN2 immunoreactivity in glutamic acid decarboxylase 65-green fluorescent protein transgenic mice, we found that HCN2-positive terminals occasionally also contact cells that contain an isoform of glutamic acid decarboxylase (glutamic acid decarboxylase 65), a marker for GABAergic inhibitory neurons. Application of ZD7288, an antagonist of HCN channels, onto neurons that were recorded in spinal cord slices with whole-cell patch-clamp electrodes reduced the number of monosynaptic excitatory postsynaptic potentials evoked by electrical stimulation of primary afferents at nociceptive intensities. The results suggest that HCN2 may contribute to the modulation of membrane excitability of SP-containing nociceptive primary afferent terminals, may increase the reliability of synaptic transmission from primary afferents to secondary sensory neurons and thus may play a role in the fine-tuning of pain transmission from nociceptive primary afferents to neurons in the spinal dorsal horn.

• Expression of hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 in axon terminals of peptidergic nociceptive primary sensory neurons in the superficial spinal dorsal horn of rats.

  Authors: Miklós Antal, Ildikó Papp, Niyazi Bahaerguli, Gábor Veress, György Vereb

  The European journal of neuroscience. 04/2004; 19(5):1336-42.

  Hyperpolarization-activated cyclic nucleotide-gated cation channel proteins (HCN1-4), which are potentially able to modulate membrane excitability, are abundantly expressed by neurons in spinalHyperpolarization-activated cyclic nucleotide-gated cation channel proteins (HCN1-4), which are potentially able to modulate membrane excitability, are abundantly expressed by neurons in spinal dorsal root ganglia (DRG). In the present experiment, we investigated whether HCN2 protein is confined exclusively to the perikarya of DRG neurons or is transported from the somata to the central axons of DRG neurons that terminate in the spinal dorsal horn. Using immunohistochemical methods, we have demonstrated that laminae I-IIo of the superficial spinal dorsal horn of the adult rat spinal cord show a strong punctate immunoreactivity for HCN2. Dorsal rhizotomy resulted in a complete loss of immunostaining in the dorsal horn, suggesting that HCN2 is confined to axon terminals of primary afferents. In double labelling immunohistochemical studies, we have also shown that HCN2 widely co-localizes with calcitonin gene-related peptide, but is almost completely segregated from isolectin-B4 binding, indicating that HCN2 is primarily expressed in peptidergic nociceptive primary afferents. The expression of HCN2 in central terminals of peptidergic primary afferents was also verified with electron microscopy. Utilizing the pre-embedding nanogold method, we found that HCN2 is largely confined to axon terminals with dense-core vesicles. Within these terminals, some of the silver grains marking the accurate location of HCN2 molecules were associated with the cell membrane, and others were scattered in the axoplasm. Within the cell membrane, HCN2 was found almost exclusively in extrasynaptic locations. The results suggest that HCN2 may contribute to the modulation of membrane excitability of nociceptive primary afferent terminals in the spinal dorsal horn.

• Gerincvelői neuronhálózatok szerveződése, pre- és posztnatális fejlődése, és plasztikus változásai neuropátiás és gyulladásos fájdalom modellekben = Organization, pre- and postnatal development of spinal neural circuits, and their plasticity in neuropathic and inflammatory pain states

  Authors: Miklós Antal, Mária Eördögh, Dóra Muszil, Ildikó Papp, Mihály Petkó, Zoltán Szabó, Karolina Szokol, Péter Szűcs, Gábor Veress

  A pályázat célul tűzte ki a gerincvelői nociceptív ingerületfeldolgozást végző és a gerincvelői szintű motoros működéseket irányító neuronhálózatok szerveződésének, kémiai tulajdonságainak, ésA pályázat célul tűzte ki a gerincvelői nociceptív ingerületfeldolgozást végző és a gerincvelői szintű motoros működéseket irányító neuronhálózatok szerveződésének, kémiai tulajdonságainak, és fájdalom modellekben mutatott plaszticitásának vizsgálatát. Ennek megfelelően vizsgáltuk a nociceptív primer afferensek és a gerincvelői hátsó szarvi másodlagos érző neuronok közötti szinaptikus kapcsolatok molekuláris anatómiáját; a gerincvelő hátsó szarvi propriospinalis neuronok szinaptikus kapcsolatait, fiziológiai és neurokémiai tulajdonságait; a gerincvelő hátsó szarvi neuronhálózatok plaszticitását gyulladásos fájdalom modellben; és a gerincvelői motoros működések szabályozásában résztvevő premotor interneuronok neurokémiai tulajdoságait. Eredményeink jelentős mértékben hozzájárultak a gerincvelői neuronok morfológia, fiziológiai és neurokémiai tulajdonságainak pontosabb megértéséhez, és ezen keresztül ahhoz, hogy pontosabb képet alkothassunk a gerincvelői neuronoknak a nociceptív és motoros feladatok kivitelezésében betöltött szerepéről. Eredményeink hozzájárultak a fájdalomérzet kiváltásában szerepet játszó gerincvelői szintű szenzoros ingerület feldolgozási folyamatok pontosabb megértéséhez. Rávilágítottuk a figyelmet olyan molekulákra, amelyek eddig nem kaptak megfelelő figyelmet a fájdalomkutatásban. Eredeti megfigyeléseink kiindulópontul szolgálhatnak újabb, az eddigieknél hatékonyabb és kevésbe addiktív fájdalomcsillapító eljárások kidolgozásához. | The aim of the project was to investigate the organization and neurochemical properties of spinal neural circuits underlying nociceptive information processing and motor control. In addition, we also intended to study the plasticity of sensory neural microcircuits of the superficial spinal dorsal horn evoked by inflammatory chronic pain. Thus, we investigated the molecular anatomy of synaptic contacts between axon terminals of nociceptive primary afferents and secondary sensory spinal neurons; synaptic interconnectivity, physiological and neurochemical properties of propriospinal neuron in the superficial spinal dorsal horn; plasticity of spinal neural microcircuits evoked by chronic subcutaneous inflammation; and the chemical properties of premotor interneurons participating in the coordination of spinal motor activities. Our results provided a substantial contribution to the understanding of the morphological, physiological and neurochemical properties of spinal neurons, and also enabled us to obtain a better understanding about nociceptive and motor activities at the level of the spinal cord. We provided new insights into the organization of pain processing spinal microcircuits, fundamental mechanisms of activity-evoked neural plasticity. We have described molecular mechanisms that have not received enough attention in pain research till now. Our original observations may assist in developing effective therapeutic strategies for chronic pain syndromes.