Abstract
ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain1. The ATP receptor P2X3 is selectively expressed by nociceptors2,3 and is one of seven ATP-gated, cation-selective ion channels4,5,6. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X2/3 heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious ‘warming’ stimuli.
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References
Bleehen T. & Keele, C. A. Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain 3, 367–377 ( 1977).
Chen, C. et al. A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377, 428–431 ( 1995).
Lewis, C. et al. Co-expression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 377 , 432–435 (1995).
MacKenzie, A. B., Surprenant, A. & North, R. A. Functional and molecular diversity of purinergic ion channel receptors. Ann. NY Acad. Sci. 30, 716–729 (1999).
Grubb, B. D. & Evans, R. J. Characterization of cultured dorsal root ganglion neuron P2X receptors. Eur. J. Neurosci. 11, 149–154 (1999).
Ueno, S., Tsuda, M., Iwanaga, T. & Inoue, K. Cell type-specific ATP-activated responses in rat dorsal root ganglion neurons. Br. J. Pharmcol. 126, 429–436 (1999).
Thomas, K. R. & Capecchi, M. R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512 (1987).
Mogil, J. S. et al. Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 80, 67–82 (1999).
Chapman, V., Ng, J. & Dickenson, A. H. A novel spinal action of mexiletine in spinal somatosensory transmission of nerve injured rats. Pain 77, 289–296 (1998).
Stanfa, L. C., Kontinen, V. K. & Dickenson, A. H. Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats. Br. J. Pharmacol. 129, 351–359 (2000).
Li, J. & Perl, E. R. ATP modulation of synaptic transmission in the spinal substantia gelatinosa. J. Neurosci. 15, 3357–3365 (1995).
Li, P., Calejesan, A. A. & Zhua, M. ATP P2X receptors and sensory synaptic transmission between primary afferent fibres and spinal dorsal horn neurons in rats. J. Neurophysiol. 80, 3356–3360 (1998).
Cesare, P. & McNaughton, P. Peripheral pain mechanisms. Curr. Opin. Neurobiol. 7, 493–499 (1997).
Tsuda, M., Ueno, S. & Inoue, K. Evidence for the involvement of spinal endogenous ATP and P2X receptors in nociceptive responses caused by formalin and capsaicin in mice. Br. J. Pharmacol. 128, 1497–1504 (1999).
Gu, J. G., Bardoni, R., Magherini, P. C. & MacDermott, A. B. Effects of the P2-purinoceptor antagonists suramin and PPADS on glutamatergic synaptic transmission in rat dorsal horn neurons of the spinal cord. Neurosci. Lett. 253, 167–170 (1998).
Gu, J. G. & MacDermott, A. B. Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 389, 749–753 ( 1997).
Bland-Ward, P. A. & Humphrey, P. P. A. Acute nociception mediated by hindpaw P2X receptor activation in the rat. Br. J. Pharmacol. 122, 365–371 (1997).
Nakamura, F. & Strittmatter, S. M. P2Y1 purinergic receptors in sensory neurons: contribution to touch-induced impulse generation. Proc. Natl Acad. Sc.i USA 17, 10465– 10470 (1996).
Kidd, E. J., Miller, K. J., Sansum, A. J. & Humphrey, P. P. Evidence for P2X3 receptors in the developing rat brain. Neuroscience 87, 533–539 ( 1998).
Cesare, P., Souslova, V., Akopian, A., Rufian, O. & Wood, J. N. Fast inactivatating responses to ATP are lost in dorsal root ganglion neurons isolated from P2X3 knock-out mice. Proc. Physiol. Soc. 523P, ( 2000).
Akopian, A. N. et al. The tetrodotoxin-resistant sodium channel SNS plays a specialised role in pain pathways. Nature Neurosci. 2, 541–548 (1999).
Acknowledgements
We thank the Wellcome Trust, EC Biomed and the MRC for support and H. Thompson for help with genotyping mice.
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Souslova, V., Cesare, P., Ding, Y. et al. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407, 1015–1017 (2000). https://doi.org/10.1038/35039526
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DOI: https://doi.org/10.1038/35039526
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