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      Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity

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          Abstract

          Background

          To evaluate whether P2X receptors are involved in responses to noxious pulp stimulation, the P2X 3 and P2X 2/3 receptor agonist α,β-methyleneATP (α,β-meATP) was applied to the molar tooth pulp and nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation in trigeminal spinal subnucleus caudalis (Vc), trigeminal spinal subnucleus interpolaris (Vi), upper cervical spinal cord (C1/C2) and paratrigeminal nucleus (Pa5) neurons were analyzed in rats.

          Results

          Genioglossus (GG) muscle activity was evoked by pulpal application of 100 mM α,β-meATP and was significantly larger than GG activity following vehicle (phosphate-buffered saline PBS) application (p < 0.01). The enhanced GG muscle activity following 100 mM α,β-meATP was significantly reduced (p < 0.05) by co-application of 1 mM TNP-ATP (P2X 1, P2X 3 and, P2X 2/3 antagonist). A large number of pERK-LI cells were expressed in the Vc, Vi/Vc, C1/C2 and Pa5 at 5 min following pulpal application of 100 mM α,β-meATP compared to PBS application to the pulp (p < 0.05). The pERK-LI cell expression and GG muscle activity induced by 100 mM α,β-meATP pulpal application were significantly reduced after intrathecal injection of the MAPK/ERK kinase (MEK) inhibitor PD 98059 and by pulpal co-application of 1 mM TNP-ATP (p < 0.05).

          Conclusions

          The present findings suggest that activation of P2X 3 and P2X 2/3 receptors in the tooth pulp is sufficient to elicit nociceptive behavioral responses and trigeminal brainstem neuronal activity.

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          Most cited references62

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          Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity.

          We investigated the involvement of extracellular signal-regulated protein kinases (ERK) within spinal neurons in producing pain hypersensitivity. Within a minute of an intense noxious peripheral or C-fiber electrical stimulus, many phosphoERK-positive neurons were observed, most predominantly in lamina I and IIo of the ipsilateral dorsal horn. This staining was intensity and NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no effect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization. ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity. Because of its rapid activation, this effect probably involves regulation of neuronal excitability without changes in transcription.
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            Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization.

            Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
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              International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits.

              ATP acts as a humoral mediator to control cell function extracellularly. The receptors that mediate the actions of ATP belong to two classes, the metabotropic P2Y receptors and the transmitter-gated, ion channel P2X receptors. This review describes the structure, distribution, function, and ligand recognition characteristics of P2X receptors, which comprise seven distinct subunits that can function as both homo- and hetero- polymers. The pharmacology of P2X receptors is complicated by marked differences between species orthologues. The current nomenclature is based largely on recombinant receptor studies and detailed knowledge of endogenous P2X receptors in native tissues is limited because of lack of good selective agonists and antagonists for each receptor type.
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                Author and article information

                Journal
                Mol Pain
                Molecular Pain
                BioMed Central
                1744-8069
                2010
                22 September 2010
                : 6
                : 59
                Affiliations
                [1 ]Department of Diagnostic & Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyaki-dai, Sakado, 350-0283, Japan
                [2 ]Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                [3 ]Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                [4 ]Department of Endodontics, Nihon University School of Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                [5 ]Department of Oral Physiology, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, M5G 1G6, Canada
                [6 ]Department of Physiology, Nihon University School of Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                [7 ]Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                [8 ]Department of Anesthesiology, Nihon University School of Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                [9 ]Oral and Maxillofacial Surgery Nihon University School of Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo, 101-8310, Japan
                Article
                1744-8069-6-59
                10.1186/1744-8069-6-59
                3146069
                20860800
                8776bae4-7f28-4b00-9919-e7d9bc135f50
                Copyright ©2010 Adachi et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 July 2010
                : 22 September 2010
                Categories
                Research

                Molecular medicine
                Molecular medicine

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