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      Sodium channel Na v1.8 immunoreactivity in painful human dental pulp

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          Abstract

          Background

          The tetrodotoxin-resistant voltage-gated sodium channel Na v1.8 (SNS1/PN3) is expressed by nociceptors and may play a role in pain states.

          Methods

          Using specific antibodies for immunohistochemistry, we studied Na v1.8 – immunoreactivity in human dental pulp in relation to the neuronal marker neurofilament. Human tooth pulp was extracted from teeth harvested from a total of twenty-two patients (fourteen without dental pain, eight patients with dental pain).

          Results

          Fibres immunoreactive for Na v1.8, were significantly increased on image analysis in the painful group: median (range) Na v1.8 to Neurofilament % area ratio, non-painful 0.059 (0.006–0.24), painful 0.265 (0.13–0.5), P = 0.0019.

          Conclusion

          Na v1.8 sodium channels may thus represent a therapeutic target in trigeminal nerve pain states.

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          Most cited references18

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          A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.

          Dorsal root ganglion sensory neurons associated with C-fibres, many of which are activated by tissue-damage, express an unusual voltage-gated sodium channel that is resistant to tetrodotoxin. We report here that we have identified a 1,957 amino-acid sodium channel in these cells that shows 65% identity with the rat cardiac tetrodotoxin-insensitive sodium channel, and is not expressed in other peripheral and central neurons, glia or non-neuronal tissues. In situ hybridization shows that the channel is expressed only by small-diameter sensory neurons in neonatal and adult dorsal root and trigeminal ganglia. The channel is resistant to tetrodotoxin when expressed in Xenopus oocytes. The electrophysiological and pharmacological properties of the expressed channel are similar to those described for the small-diameter sensory neuron tetrodotoxin-resistant sodium channels. As some noxious input into the spinal cord is resistant to tetrodotoxin, block of expression or function of such a C-fibre-restricted sodium channel may have a selective analgesic effect.
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            Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8.

            Neuropathic pain is a debilitating chronic syndrome that often arises from injuries to peripheral nerves. Such pain has been hypothesized to be the result of an aberrant expression and function of sodium channels at the site of injury. Here, we show that intrathecal administration of specific antisense oligodeoxynucleotides (ODN) to the peripheral tetrodotoxin (TTX)-resistant sodium channel, NaV1.8, resulted in a time-dependent uptake of the ODN by dorsal root ganglion (DRG) neurons, a selective "knock-down" of the expression of NaV1.8, and a reduction in the slow-inactivating, TTX-resistant sodium current in the DRG cells. The ODN treatment also reversed neuropathic pain induced by spinal nerve injury, without affecting non-noxious sensation or response to acute pain. These data provide direct evidence linking NaV1.8 to neuropathic pain. As NaV1.8 expression is restricted to sensory neurons, this channel offers a highly specific and effective molecular target for the treatment of neuropathic pain.
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              Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states.

              The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel SNS/PN3 and the newly discovered NaN/SNS2 are expressed in sensory neurones, particularly in nociceptors. Using specific antibodies, we have studied, for the first time in humans, the presence of SNS/PN3 and NaN/SNS2 in peripheral nerves, including tissues from patients with chronic neurogenic pain. In brachial plexus injury patients, there was an acute decrease of SNS/PN3- and NaN/SNS2-like immunoreactivity in sensory cell bodies of cervical dorsal root ganglia (DRG) whose central axons had been avulsed from spinal cord, with gradual return of the immunoreactivity to control levels over months. In contrast, there was increased intensity of immunoreactivity to both channels in some peripheral nerve fibers just proximal to the site of injury in brachial plexus trunks, and in neuromas. These findings suggest that the expression of these sodium channels in neuronal cell bodies is reduced after spinal cord root avulsion injury in man, but that pre-synthesized channel proteins may undergo translocation with accumulation at sites of nerve injury, as in animal models of peripheral axotomy. The latter may contribute to positive symptoms, as our patients all showed a positive Tinel's sign. Nerve terminals in distal limb neuromas and skin from patients with chronic local hyperalgesia and allodynia all showed marked increases of SNS/PN3-immunoreactive fibers, but little or no NaN/SNS2-immunoreactivity, suggesting that the former may be related to the persistent hypersensitive state. Axonal immunoreactivity to both channels was similar to control nerves in sural nerve biopsies in a selection of neuropathies, irrespective of nerve inflammation, demyelination or spontaneous pain, including a patient with congenital insensitivity to pain. Our studies suggest that the best target for SNS/PN3 blocking agents is likely to be chronic local hypersensitivity.
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                Author and article information

                Journal
                BMC Oral Health
                BMC Oral Health
                BioMed Central (London )
                1472-6831
                2005
                7 July 2005
                : 5
                : 5
                Affiliations
                [1 ]Department of Oral & Maxillofacial Surgery, Dental Institute, Queen Mary's College, London University, Whitechapel, London UK
                [2 ]Peripheral Neuropathy Unit, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK
                [3 ]GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
                [4 ]Neurology-CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK
                Article
                1472-6831-5-5
                10.1186/1472-6831-5-5
                1183220
                16001984
                e8059bbc-e12b-4fa2-898d-441917b833a1
                Copyright © 2005 Renton 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
                : 24 December 2004
                : 7 July 2005
                Categories
                Research Article

                Dentistry
                Dentistry

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