Skip to main content
Top
Published in: Molecular Pain 1/2011

Open Access 01-12-2011 | Research

Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats

Authors: Guang-Yin Xu, Guangwen Li, Ningang Liu, Li-Yen Mae Huang

Published in: Molecular Pain | Issue 1/2011

Login to get access

Abstract

Background

Diabetic neuropathy is a common neuropathy associated with paresthaesia and pain. The mechanisms underlying the painful conditions are not well understood. The aim of this study is to investigate the participation of purinergic P2X3 receptors in painful diabetic neuropathy.

Results

Diabetes was induced by an intraperitoneal injection of streptozotocin (STZ). We showed that mechanical allodynia was induced two weeks after a STZ injection and lasted for at least another seven weeks. The mechanical allodynia was significantly attenuated by peripheral administration of the P2X receptor antagonists, PPADS or TNP-ATP. DiI was subcutaneously injected into the rat hindpaw to label hindpaw-innervated dorsal root ganglion (DRG) neurons. ATP activated fast-inactivating P2X3 receptor-mediated currents in the labeled DRG neurons were studied. ATP responses in STZ-treated rats were ~2-fold larger than those in control rats. Furthermore, the expression of P2X3 receptor proteins in the plasma membrane of L4-6 DRGs of STZ rats was significantly enhanced while the total expression of P2X3 receptors remained unaltered.

Conclusions

These results indicate that a large enhancement of P2X3 receptor activity and an increase in the membrane expression of P2X3 receptors contribute to the development of chronic pain in STZ-induced diabetic rats and suggest a possible target for the treatment of diabetic neuropathic pain.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ, Service FJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993, 43: 817–824.PubMedCrossRef Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ, Service FJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993, 43: 817–824.PubMedCrossRef
3.
go back to reference Harati Y: Diabetes and the nervous system. Endocrinol Metab Clin North Am 1996, 25: 325–359. 10.1016/S0889-8529(05)70327-3PubMedCrossRef Harati Y: Diabetes and the nervous system. Endocrinol Metab Clin North Am 1996, 25: 325–359. 10.1016/S0889-8529(05)70327-3PubMedCrossRef
4.
go back to reference Khan GM, Chen SR, Pan HL: Role of primary afferent nerves in allodynia caused by diabetic neuropathy in rats. Neuroscience 2002, 114: 291–299. 10.1016/S0306-4522(02)00372-XPubMedCrossRef Khan GM, Chen SR, Pan HL: Role of primary afferent nerves in allodynia caused by diabetic neuropathy in rats. Neuroscience 2002, 114: 291–299. 10.1016/S0306-4522(02)00372-XPubMedCrossRef
5.
go back to reference Gooch C, Podwall D: The diabetic neuropathies. Neurologist 2004, 10: 311–322. 10.1097/01.nrl.0000144733.61110.25PubMedCrossRef Gooch C, Podwall D: The diabetic neuropathies. Neurologist 2004, 10: 311–322. 10.1097/01.nrl.0000144733.61110.25PubMedCrossRef
6.
go back to reference Pabbidi RM, Cao DS, Parihar A, Pauza ME, Premkumar LS: Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons. Mol Pharmacol 2008, 73: 995–1004.PubMedCrossRef Pabbidi RM, Cao DS, Parihar A, Pauza ME, Premkumar LS: Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons. Mol Pharmacol 2008, 73: 995–1004.PubMedCrossRef
7.
go back to reference Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, Bayliss DA, Jevtovic-Todorovic V, Todorovic SM: Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci 2007, 27: 3305–3316. 10.1523/JNEUROSCI.4866-06.2007PubMedCrossRef Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, Bayliss DA, Jevtovic-Todorovic V, Todorovic SM: Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci 2007, 27: 3305–3316. 10.1523/JNEUROSCI.4866-06.2007PubMedCrossRef
8.
go back to reference Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS: Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 2008, 4: 9. 10.1186/1744-8069-4-9PubMedCentralPubMedCrossRef Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS: Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 2008, 4: 9. 10.1186/1744-8069-4-9PubMedCentralPubMedCrossRef
9.
go back to reference Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW: Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 1997, 387: 505–508. 10.1038/387505a0PubMedCrossRef Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW: Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 1997, 387: 505–508. 10.1038/387505a0PubMedCrossRef
10.
go back to reference Petruska JC, Cooper BY, Johnson RD, Gu JG: Distribution patterns of different P2x receptor phenotypes in acutely dissociated dorsal root ganglion neurons of adult rats. Exp Brain Res 2000, 134: 126–132. 10.1007/s002210000414PubMedCrossRef Petruska JC, Cooper BY, Johnson RD, Gu JG: Distribution patterns of different P2x receptor phenotypes in acutely dissociated dorsal root ganglion neurons of adult rats. Exp Brain Res 2000, 134: 126–132. 10.1007/s002210000414PubMedCrossRef
11.
12.
go back to reference Xu GY, Huang LY: Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 2002, 22: 93–102.PubMed Xu GY, Huang LY: Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 2002, 22: 93–102.PubMed
14.
go back to reference Chen Y, Li GW, Wang C, Gu Y, Huang LY: Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain 2005, 119: 38–48. 10.1016/j.pain.2005.09.007PubMedCrossRef Chen Y, Li GW, Wang C, Gu Y, Huang LY: Mechanisms underlying enhanced P2X receptor-mediated responses in the neuropathic pain state. Pain 2005, 119: 38–48. 10.1016/j.pain.2005.09.007PubMedCrossRef
15.
go back to reference Bardoni R, Goldstein PA, Lee CJ, Gu JG, MacDermott AB: ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J Neurosci 1997, 17: 5297–5304.PubMed Bardoni R, Goldstein PA, Lee CJ, Gu JG, MacDermott AB: ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J Neurosci 1997, 17: 5297–5304.PubMed
16.
go back to reference Burnstock G: Purinergic receptors and pain. Curr Pharm Des 2009, 15: 1717–1735. 10.2174/138161209788186335PubMedCrossRef Burnstock G: Purinergic receptors and pain. Curr Pharm Des 2009, 15: 1717–1735. 10.2174/138161209788186335PubMedCrossRef
17.
go back to reference Kennedy C, McLaren GJ, Westfall TD, Sneddon P: ATP as a co-transmitter with noradrenaline in sympathetic nerves--function and fate. Ciba Found Symp 1996, 198: 223–235. discussion 235–228PubMed Kennedy C, McLaren GJ, Westfall TD, Sneddon P: ATP as a co-transmitter with noradrenaline in sympathetic nerves--function and fate. Ciba Found Symp 1996, 198: 223–235. discussion 235–228PubMed
18.
go back to reference Sato J, Kumazawa T: Sympathetic modulation of cutaneous polymodal receptors in chronically inflamed and diabetic rats. Prog Brain Res 1996, 113: 153–159.PubMedCrossRef Sato J, Kumazawa T: Sympathetic modulation of cutaneous polymodal receptors in chronically inflamed and diabetic rats. Prog Brain Res 1996, 113: 153–159.PubMedCrossRef
19.
go back to reference Lynch JJ, Jarvis MF, Kowaluk EA: An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain. Eur J Pharmacol 1999, 364: 141–146. 10.1016/S0014-2999(98)00840-1PubMedCrossRef Lynch JJ, Jarvis MF, Kowaluk EA: An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain. Eur J Pharmacol 1999, 364: 141–146. 10.1016/S0014-2999(98)00840-1PubMedCrossRef
20.
go back to reference Migita K, Moriyama T, Koguchi M, Honda K, Katsuragi T, Takano Y, Ueno S: Modulation of P2X receptors in dorsal root ganglion neurons of streptozotocin-induced diabetic neuropathy. Neurosci Lett 2009, 452: 200–203. 10.1016/j.neulet.2009.01.048PubMedCrossRef Migita K, Moriyama T, Koguchi M, Honda K, Katsuragi T, Takano Y, Ueno S: Modulation of P2X receptors in dorsal root ganglion neurons of streptozotocin-induced diabetic neuropathy. Neurosci Lett 2009, 452: 200–203. 10.1016/j.neulet.2009.01.048PubMedCrossRef
21.
go back to reference Rerup CC: Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 1970, 22: 485–518.PubMed Rerup CC: Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 1970, 22: 485–518.PubMed
22.
go back to reference Ahlgren SC, Levine JD: Mechanical hyperalgesia in streptozotocin-diabetic rats. Neuroscience 1993, 52: 1049–1055. 10.1016/0306-4522(93)90551-PPubMedCrossRef Ahlgren SC, Levine JD: Mechanical hyperalgesia in streptozotocin-diabetic rats. Neuroscience 1993, 52: 1049–1055. 10.1016/0306-4522(93)90551-PPubMedCrossRef
23.
go back to reference Malcangio M, Tomlinson DR: A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 1998, 76: 151–157. 10.1016/S0304-3959(98)00037-2PubMedCrossRef Malcangio M, Tomlinson DR: A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 1998, 76: 151–157. 10.1016/S0304-3959(98)00037-2PubMedCrossRef
24.
go back to reference Xu GY, Huang LY: Ca2+/calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc Natl Acad Sci USA 2004, 101: 11868–11873. 10.1073/pnas.0401490101PubMedCentralPubMedCrossRef Xu GY, Huang LY: Ca2+/calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc Natl Acad Sci USA 2004, 101: 11868–11873. 10.1073/pnas.0401490101PubMedCentralPubMedCrossRef
25.
go back to reference Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55–63. 10.1016/0165-0270(94)90144-9PubMedCrossRef Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55–63. 10.1016/0165-0270(94)90144-9PubMedCrossRef
27.
go back to reference Honore P, Mikusa J, Bianchi B, McDonald H, Cartmell J, Faltynek C, Jarvis MF: TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics. Pain 2002, 96: 99–105. 10.1016/S0304-3959(01)00434-1PubMedCrossRef Honore P, Mikusa J, Bianchi B, McDonald H, Cartmell J, Faltynek C, Jarvis MF: TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics. Pain 2002, 96: 99–105. 10.1016/S0304-3959(01)00434-1PubMedCrossRef
28.
go back to reference Xiang Z, Bo X, Burnstock G: Localization of ATP-gated P2X receptor immunoreactivity in rat sensory and sympathetic ganglia. Neurosci Lett 1998, 256: 105–108. 10.1016/S0304-3940(98)00774-5PubMedCrossRef Xiang Z, Bo X, Burnstock G: Localization of ATP-gated P2X receptor immunoreactivity in rat sensory and sympathetic ganglia. Neurosci Lett 1998, 256: 105–108. 10.1016/S0304-3940(98)00774-5PubMedCrossRef
29.
go back to reference Burnstock G, Wood JN: Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr Opin Neurobiol 1996, 6: 526–532. 10.1016/S0959-4388(96)80060-2PubMedCrossRef Burnstock G, Wood JN: Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr Opin Neurobiol 1996, 6: 526–532. 10.1016/S0959-4388(96)80060-2PubMedCrossRef
30.
go back to reference McGaraughty S, Wismer CT, Zhu CZ, Mikusa J, Honore P, Chu KL, Lee CH, Faltynek CR, Jarvis MF: Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration. Br J Pharmacol 2003, 140: 1381–1388. 10.1038/sj.bjp.0705574PubMedCentralPubMedCrossRef McGaraughty S, Wismer CT, Zhu CZ, Mikusa J, Honore P, Chu KL, Lee CH, Faltynek CR, Jarvis MF: Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration. Br J Pharmacol 2003, 140: 1381–1388. 10.1038/sj.bjp.0705574PubMedCentralPubMedCrossRef
31.
go back to reference Nakatsuka T, Gu JG: P2X purinoceptors and sensory transmission. Pflugers Arch 2006, 452: 598–607. 10.1007/s00424-006-0057-6PubMedCrossRef Nakatsuka T, Gu JG: P2X purinoceptors and sensory transmission. Pflugers Arch 2006, 452: 598–607. 10.1007/s00424-006-0057-6PubMedCrossRef
32.
go back to reference Tsuda M, Tozaki-Saitoh H, Inoue K: Pain and purinergic signaling. Brain Res Rev 2009. Tsuda M, Tozaki-Saitoh H, Inoue K: Pain and purinergic signaling. Brain Res Rev 2009.
33.
go back to reference Gao Y, Xu C, Yu K, Li G, Wan F, Liu S, Lin J, Liu H, Zhang J, Li X, Liang S: Effect of tetramethylpyrazine on DRG neuron P2X(3) receptor involved in transmitting pain after burn. Burns 2009, 36: 127–134.PubMedCrossRef Gao Y, Xu C, Yu K, Li G, Wan F, Liu S, Lin J, Liu H, Zhang J, Li X, Liang S: Effect of tetramethylpyrazine on DRG neuron P2X(3) receptor involved in transmitting pain after burn. Burns 2009, 36: 127–134.PubMedCrossRef
34.
go back to reference Xiang Z, Xiong Y, Yan N, Li X, Mao Y, Ni X, He C, LaMotte RH, Burnstock G, Sun J: Functional up-regulation of P2X 3 receptors in the chronically compressed dorsal root ganglion. Pain 2008, 140: 23–34. 10.1016/j.pain.2008.07.006PubMedCentralPubMedCrossRef Xiang Z, Xiong Y, Yan N, Li X, Mao Y, Ni X, He C, LaMotte RH, Burnstock G, Sun J: Functional up-regulation of P2X 3 receptors in the chronically compressed dorsal root ganglion. Pain 2008, 140: 23–34. 10.1016/j.pain.2008.07.006PubMedCentralPubMedCrossRef
35.
go back to reference Petruska JC, Mena N, Nakatsuka T, Cooper BY, Johnson RD, Gu JG: P2X1 receptor subunit immunoreactivity and ATP-evoked fast currents in adult rat dorsal root ganglion neurons. Neuroreport 2000, 11: 3589–3592. 10.1097/00001756-200011090-00037PubMedCrossRef Petruska JC, Mena N, Nakatsuka T, Cooper BY, Johnson RD, Gu JG: P2X1 receptor subunit immunoreactivity and ATP-evoked fast currents in adult rat dorsal root ganglion neurons. Neuroreport 2000, 11: 3589–3592. 10.1097/00001756-200011090-00037PubMedCrossRef
36.
go back to reference Kobayashi K, Fukuoka T, Yamanaka H, Dai Y, Obata K, Tokunaga A, Noguchi K: Differential expression patterns of mRNAs for P2X receptor subunits in neurochemically characterized dorsal root ganglion neurons in the rat. J Comp Neurol 2005, 481: 377–390. 10.1002/cne.20393PubMedCrossRef Kobayashi K, Fukuoka T, Yamanaka H, Dai Y, Obata K, Tokunaga A, Noguchi K: Differential expression patterns of mRNAs for P2X receptor subunits in neurochemically characterized dorsal root ganglion neurons in the rat. J Comp Neurol 2005, 481: 377–390. 10.1002/cne.20393PubMedCrossRef
37.
go back to reference Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K: P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003, 424: 778–783. 10.1038/nature01786PubMedCrossRef Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K: P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003, 424: 778–783. 10.1038/nature01786PubMedCrossRef
38.
go back to reference Inoue K, Tsuda M, Koizumi S: ATP receptors in pain sensation: Involvement of spinal microglia and P2X(4) receptors. Purinergic Signal 2005, 1: 95–100. 10.1007/s11302-005-6210-4PubMedCentralPubMedCrossRef Inoue K, Tsuda M, Koizumi S: ATP receptors in pain sensation: Involvement of spinal microglia and P2X(4) receptors. Purinergic Signal 2005, 1: 95–100. 10.1007/s11302-005-6210-4PubMedCentralPubMedCrossRef
39.
go back to reference Inoue K, Tsuda M, Tozaki-Saitoh H: Modification of neuropathic pain sensation through microglial ATP receptors. Purinergic Signal 2007, 3: 311–316. 10.1007/s11302-007-9071-1PubMedCentralPubMedCrossRef Inoue K, Tsuda M, Tozaki-Saitoh H: Modification of neuropathic pain sensation through microglial ATP receptors. Purinergic Signal 2007, 3: 311–316. 10.1007/s11302-007-9071-1PubMedCentralPubMedCrossRef
40.
go back to reference Zhang X, Chen Y, Wang C, Huang LY: Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci USA 2007, 104: 9864–9869. 10.1073/pnas.0611048104PubMedCentralPubMedCrossRef Zhang X, Chen Y, Wang C, Huang LY: Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci USA 2007, 104: 9864–9869. 10.1073/pnas.0611048104PubMedCentralPubMedCrossRef
41.
go back to reference Novakovic SD, Kassotakis LC, Oglesby IB, Smith JA, Eglen RM, Ford AP, Hunter JC: Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 1999, 80: 273–282. 10.1016/S0304-3959(98)00225-5PubMedCrossRef Novakovic SD, Kassotakis LC, Oglesby IB, Smith JA, Eglen RM, Ford AP, Hunter JC: Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 1999, 80: 273–282. 10.1016/S0304-3959(98)00225-5PubMedCrossRef
42.
go back to reference Bradbury EJ, Burnstock G, McMahon SB: The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 1998, 12: 256–268. 10.1006/mcne.1998.0719PubMedCrossRef Bradbury EJ, Burnstock G, McMahon SB: The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 1998, 12: 256–268. 10.1006/mcne.1998.0719PubMedCrossRef
43.
go back to reference Wang R, Guo W, Ossipov MH, Vanderah TW, Porreca F, Lai J: Glial cell line-derived neurotrophic factor normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain. Neuroscience 2003, 121: 815–824. 10.1016/S0306-4522(03)00491-3PubMedCrossRef Wang R, Guo W, Ossipov MH, Vanderah TW, Porreca F, Lai J: Glial cell line-derived neurotrophic factor normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain. Neuroscience 2003, 121: 815–824. 10.1016/S0306-4522(03)00491-3PubMedCrossRef
Metadata
Title
Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats
Authors
Guang-Yin Xu
Guangwen Li
Ningang Liu
Li-Yen Mae Huang
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-7-60

Other articles of this Issue 1/2011

Molecular Pain 1/2011 Go to the issue