QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, September 22, 2004, 24(38):8300-8309; doi:10.1523/JNEUROSCI.2893-04.2004

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (101) Citing Articles via Google Scholar Google Scholar Articles by Zhuang, Z.-Y. Articles by Ji, R.-R. Search for Related Content PubMed PubMed Citation Articles by Zhuang, Z.-Y. Articles by Ji, R.-R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CAPSAICIN

 Previous Article  |  Next Article 

Development/Plasticity/Repair
Phosphatidylinositol 3-Kinase Activates ERK in Primary Sensory Neurons and Mediates Inflammatory Heat Hyperalgesia through TRPV1 Sensitization

Zhi-Ye Zhuang,¹ Haoxing Xu,² David E. Clapham,² and Ru-Rong Ji¹

¹Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and ²Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Although the PI3K (phosphatidylinositol 3-kinase) pathway typically regulates cell growth and survival, increasing evidence indicates the involvement of this pathway in neural plasticity. It is unknown whether the PI3K pathway can mediate pain hypersensitivity. Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 (transient receptor potential vanilloid receptor-1) and TrkA receptors on nociceptor sensory nerve terminals. We examined the activation of PI3K in primary sensory DRG neurons by these inflammatory agents and the contribution of PI3K activation to inflammatory pain. We further investigated the correlation between the PI3K and the ERK (extracellular signal-regulated protein kinase) pathway. Capsaicin and NGF induce phosphorylation of the PI3K downstream target AKT (protein kinase B), which is blocked by the PI3K inhibitors LY294002 and wortmannin, indicative of the activation of PI3K by both agents. ERK activation by capsaicin and NGF was also blocked by PI3K inhibitors. Similarly, intradermal capsaicin in rats activated PI3K and ERK in C-fiber DRG neurons and epidermal nerve fibers. Injection of PI3K or MEK (ERK kinase) inhibitors into the hindpaw attenuated capsaicin- and NGF-evoked heat hyperalgesia but did not change basal heat sensitivity. Furthermore, PI3K, but not ERK, inhibition blocked early induction of hyperalgesia. In acutely dissociated DRG neurons, the capsaicin-induced TRPV1 current was strikingly potentiated by NGF, and this potentiation was completely blocked by PI3K inhibitors and primarily suppressed by MEK inhibitors. Therefore, PI3K induces heat hyperalgesia, possibly by regulating TRPV1 activity, in an ERK-dependent manner. The PI3K pathway also appears to play a role that is distinct from ERK by regulating the early onset of inflammatory pain.

Key words: PI3K; ERK; capsaicin; NGF; dorsal root ganglion; inflammatory pain

---

Received July 16, 2004; revised August 16, 2004; accepted August 17, 2004.

This article has been cited by other articles:

				M.-L. Sixt, K. Messlinger, and M. J. M. Fischer Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus Brain, November 1, 2009; 132(11): 3134 - 3141. [Abstract] [Full Text] [PDF]

				M. Andratsch, N. Mair, C. E. Constantin, N. Scherbakov, C. Benetti, S. Quarta, C. Vogl, C. A. Sailer, N. Uceyler, J. Brockhaus, et al. A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain J. Neurosci., October 28, 2009; 29(43): 13473 - 13483. [Abstract] [Full Text] [PDF]

				V. Bockhart, C. E. Constantin, A. Haussler, N. Wijnvoord, M. Kanngiesser, T. Myrczek, G. Pickert, L. Popp, J.-M. Sobotzik, M. Pasparakis, et al. Inhibitor {kappa}B Kinase {beta} Deficiency in Primary Nociceptive Neurons Increases TRP Channel Sensitivity J. Neurosci., October 14, 2009; 29(41): 12919 - 12929. [Abstract] [Full Text] [PDF]

				R. D'Mello and A. H. Dickenson Spinal cord mechanisms of pain Br. J. Anaesth., July 1, 2008; 101(1): 8 - 16. [Abstract] [Full Text] [PDF]

				S. D. Guerios, Z.-Y. Wang, K. Boldon, W. Bushman, and D. E. Bjorling Blockade of NGF and trk receptors inhibits increased peripheral mechanical sensitivity accompanying cystitis in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R111 - R122. [Abstract] [Full Text] [PDF]

				Y. Chen, C. Geis, and C. Sommer Activation of TRPV1 Contributes to Morphine Tolerance: Involvement of the Mitogen-Activated Protein Kinase Signaling Pathway J. Neurosci., May 28, 2008; 28(22): 5836 - 5845. [Abstract] [Full Text] [PDF]

				S. Pezet, F. Marchand, R. D'Mello, J. Grist, A. K. Clark, M. Malcangio, A. H. Dickenson, R. J. Williams, and S. B. McMahon Phosphatidylinositol 3-Kinase Is a Key Mediator of Central Sensitization in Painful Inflammatory Conditions J. Neurosci., April 16, 2008; 28(16): 4261 - 4270. [Abstract] [Full Text] [PDF]

				N.-H. Feng, H.-H. Lee, J.-C. Shiang, and M.-C. Ma Transient receptor potential vanilloid type 1 channels act as mechanoreceptors and cause substance P release and sensory activation in rat kidneys Am J Physiol Renal Physiol, February 1, 2008; 294(2): F316 - F325. [Abstract] [Full Text] [PDF]

				W. Zhu, P. Xu, F. X. Cuascut, A. K. Hall, and G. S. Oxford Activin Acutely Sensitizes Dorsal Root Ganglion Neurons and Induces Hyperalgesia via PKC-Mediated Potentiation of Transient Receptor Potential Vanilloid I J. Neurosci., December 12, 2007; 27(50): 13770 - 13780. [Abstract] [Full Text] [PDF]

				M. D'Arco, R. Giniatullin, M. Simonetti, A. Fabbro, A. Nair, A. Nistri, and E. Fabbretti Neutralization of Nerve Growth Factor Induces Plasticity of ATP-Sensitive P2X3 Receptors of Nociceptive Trigeminal Ganglion Neurons J. Neurosci., August 1, 2007; 27(31): 8190 - 8201. [Abstract] [Full Text] [PDF]

				H. J. Kim, Y. Lee, E.-J. Chang, H.-M. Kim, S.-P. Hong, Z. H. Lee, J. Ryu, and H.-H. Kim Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action Mol. Pharmacol., August 1, 2007; 72(2): 418 - 428. [Abstract] [Full Text] [PDF]

				B. Voss, J. N. McLaughlin, M. Holinstat, R. Zent, and H. E. Hamm PAR1, but Not PAR4, Activates Human Platelets through a Gi/o/Phosphoinositide-3 Kinase Signaling Axis Mol. Pharmacol., May 1, 2007; 71(5): 1399 - 1406. [Abstract] [Full Text] [PDF]

				G. D. Nicol and M. R. Vasko Unraveling the Story of NGF-mediated Sensitization of Nociceptive Sensory Neurons: ON or OFF the Trks? Mol. Interv., February 1, 2007; 7(1): 26 - 41. [Abstract] [Full Text] [PDF]

				B. Nilius, G. Owsianik, T. Voets, and J. A. Peters Transient Receptor Potential Cation Channels in Disease Physiol Rev, January 1, 2007; 87(1): 165 - 217. [Abstract] [Full Text] [PDF]

				H. L. Rittner, D. Labuz, M. Schaefer, S. A. Mousa, S. Schulz, M. Schafer, C. Stein, and A. Brack Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells FASEB J, December 1, 2006; 20(14): 2627 - 2629. [Abstract] [Full Text] [PDF]

				A. T. Stein, C. A. Ufret-Vincenty, L. Hua, L. F. Santana, and S. E. Gordon Phosphoinositide 3-Kinase Binds to TRPV1 and Mediates NGF-stimulated TRPV1 Trafficking to the Plasma Membrane J. Gen. Physiol., November 1, 2006; 128(5): 509 - 522. [Abstract] [Full Text] [PDF]

				X. Zhang and P. A. McNaughton Why Pain Gets Worse: The Mechanism of Heat Hyperalgesia J. Gen. Physiol., November 1, 2006; 128(5): 491 - 493. [Full Text] [PDF]

				W. Ma, J.-G. Chabot, and R. Quirion A role for adrenomedullin as a pain-related peptide in the rat PNAS, October 24, 2006; 103(43): 16027 - 16032. [Abstract] [Full Text] [PDF]

				A. Diogenes, A. M. Patwardhan, N. A. Jeske, N. B. Ruparel, V. Goffin, A. N. Akopian, and K. M. Hargreaves Prolactin Modulates TRPV1 in Female Rat Trigeminal Sensory Neurons J. Neurosci., August 2, 2006; 26(31): 8126 - 8136. [Abstract] [Full Text] [PDF]

				L. Negri, R. Lattanzi, E. Giannini, M. Colucci, F. Margheriti, P. Melchiorri, V. Vellani, H. Tian, M. De Felice, and F. Porreca Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior. J. Neurosci., June 21, 2006; 26(25): 6716 - 6727. [Abstract] [Full Text] [PDF]

				Y. Wang, G. D. Nicol, D. W. Clapp, and C. M. Hingtgen Sensory Neurons From Nf1 Haploinsufficient Mice Exhibit Increased Excitability J Neurophysiol, December 1, 2005; 94(6): 3670 - 3676. [Abstract] [Full Text] [PDF]

				D. E. Clapham, D. Julius, C. Montell, and G. Schultz International Union of Pharmacology. XLIX. Nomenclature and Structure-Function Relationships of Transient Receptor Potential Channels Pharmacol. Rev., December 1, 2005; 57(4): 427 - 450. [Full Text] [PDF]

				B. Nilius, T. Voets, and J. Peters TRP Channels in Disease Sci. Signal., August 2, 2005; 2005(295): re8 - re8. [Abstract] [Full Text] [PDF]

				B. Liu, C. Zhang, and F. Qin Functional Recovery from Desensitization of Vanilloid Receptor TRPV1 Requires Resynthesis of Phosphatidylinositol 4,5-Bisphosphate J. Neurosci., May 11, 2005; 25(19): 4835 - 4843. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help