Abstract
Injury to the peripheral nervous system can lead to spontaneous pain, hyperalgesia and allodynia. Previous studies have shown sprouting of Aβ-fibres into lamina II of the spinal cord dorsal horn after nerve injury and the formation of new synapses by these sprouts. β-Catenin and menin as synaptogenic factors are critically involved in synapse formation. However, the roles of β-catenin and menin in neuropathic pain are still unclear. Using Western blot analysis we investigated the changes of β-catenin and menin in the spinal dorsal horn after unilateral spared nerve injury (SNI). We demonstrated an increase in both β-catenin and menin protein levels in the ipsilateral spinal dorsal horn at days 1 and 3 following spared nerve injury (P < 0.05). These increases were associated with changes in paw withdrawal threshold to mechanical stimuli and weight bearing deficit suggestive of pain behavior and spontaneous ongoing pain respectively. However, the injury-associated increases in β-catenins and menins levels returned to control levels at day 14. In conclusion, these results indicate that peripheral nerve injury induces upregulation of β-catenins and menins in the dorsal horn of the spinal cord, which may contribute to the development of chronic neuropathic pain. Antagonists of these molecules may serve as new therapeutic agents.
Similar content being viewed by others
References
Abe K, Takeichi M (2007) NMDA-receptor activation induces Calpain-mediated β-catenin cleavages for triggering gene expression. Neuron 53:387–397
Bamji SX, Shimazu K, Kimes N, Huelsken J, Birchmeier W, Lu B, Reichardt LF (2003) Role of β-catenin in synaptic vesicle localization and presynaptic assembly. Neuron 40:719–731
Bennett AD, Everhart AW, Hulsebosch CE (2000) Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury. Brain Res 859:72–82
Bleakman D, Alt A, Nisenbaum E (2006) Glutamate receptors and pain. Semin Cell Dev Biol 17:592–604
Cao Y, Liu R, Jiang X, Lu J, Jiang J, Zhang C, Li X, Ning G (2009) Nuclear-cytoplasmic shuttling of menin regulates nuclear translocation of β-catenin. Mol Cell Biol 29:5477–5487
Chandrasekharappa SC, Guru SC, Manickam P et al (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407
Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233
Chen GAJ, Wang M, Farley S, Lee LY, Lee LC, Sawicki MP (2008) Menin promotes the Wnt signaling pathway in pancreatic endocrine cells. Mol Cancer Res 6:1894–1907
Chizh BA, Headley PM (2005) NMDA antagonists and neuropathic pain-multiple drug targets and multiple uses. Curr Pharm Des 11:2977–2994
Choua AK, Muhammada R, Huanga SM, Chena JT, Wu CL, Lin CR, Lee TH et al (2002) Altered synaptophysin expression in the rat spinal cord after chronic constriction injury of sciatic nerve. Neurosci Lett 333:155–158
Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149–158
Devor M (1994) The pathophysiology of damaged peripheral nerves. Churchill Livingstone, London
Esper RM, Loeb JA (2004) Rapid axoglial signaling mediated by neuregulin and neurotrophic factors. J Neurosci 24:6218–6227
Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, Sanai N, Franklin RJ, Rowitch DH (2009) Dysregulation of the Wnt pathway inhibit timely myelination and remyelination in the mammalian CNS. Genes Dev 23:1571–1585
Fundytus ME (2001) Glutamate receptors and nociception: implications for the drug treatment of pain. CNS Drugs 15:29–58
Gess B, Halfter H, Kleffner I, Monje P, Athauda G, Wood PM, Young P, Wanner IB (2008) Inhibition of N-Cadherin and β-catenin function reduces axon-induced schwann cell proliferation. J Neurosci Res 86:797–812
Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG (2004) Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci 24:4832–4839
Hoke A, Redett R, Hameed H, Jari R, Zhou C, Li ZB, Griffin JW, Brushart TM (2006) Schwann cells express motor and sensory phenotypes that regulate axon regeneration. J Neurosci 26:9646–9655
Jänig W, Grossmann L, Gorodetskaya N (2009) Mechano- and thermosensitivity of regenerating cutaneous afferent nerve fibers. Exp Brain Res 196:101–114
Kennedy MB, Beale HC, Carlisle HJ, Washburn LR (2005) Integration of biochemical signalling in spines. Nat Rev Neurosci 6:423–434
Kwiatkowski AV, Weis WI, Nelson WJ (2007) Catenins: playing both sides of the synapse. Curr Opin Cell Biol 19:551–556
Lekan HA, Carlton SM, Coggeshall RE (1996) Sprouting of A-[β] fibers into lamina II of the rat dorsal horn in peripheral neuropathy. Neurosci Lett 208:147–150
Miller RH (2002) Regulation of oligodendrocyte development in the vertebrate CNS. Prog Neurobiol 67:451–467
Murase S, Mosser E, Schuman EM (2002) Depolarization drives β-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35:91–105
Nakazato-Imasato E, Kurebayashi Y (2009) Pharmacological characteristics of the hind paw weight bearing difference induced by chronic constriction injury of the sciatic nerve in rats. Life Sci 84:622–626
Salter MW (2005) Cellular signalling pathways of spinal pain neuroplasticity as targets for analgesic development. Curr Top Med Chem 5:557–567
Sawicki M, Chen G, Farley S (2008) Menin is a β-catenin associated agonist of the wnt signaling pathway in pancreatic endocrine cells. J Surg Res 144:196–196
Schmeisser MJ, Grabrucker AM, Bockmann J, Boeckers TM (2009) Synaptic crosstalk between NMDA receptors andLAPSER1/β-catenin at excitatory synapses. J Biol Chem 284:29146–29157
Schoffnegger D, Ruscheweyh R, Sandkühler J (2008) Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. Pain 135:300–310
Segal M (2005) Dendritic spines and long-term plasticity. Nat Rev Neurosci 6:277–284
Song XJ, Vizcarra C, Xu DS, Rupert RL, Wong ZN (2003) Hyperalgesia and neural excitability following injuries to central and peripheral branches of axons and somata of dorsal root ganglion neurons. J Neurophysiol 89:2185–2193
Sun Y, Aiga M, Yoshida E, Humbert PO, Bamji SX (2009) Scribble interacts with β-catenin to localize synapti vesicles to synapses. Mol Biol Cell 20:3390–3400
Van Kesteren RE, Syed NI, Munno DW, Bouwman J, Feng ZP, Geraerts WP, Smit AB (2001) Synapse formation between central neurons requires postsynaptic expression of the MEN1 tumor suppressor gene. J Neurosci 21:1–5
Woolf CJ (2007) Central sensitization: uncovering the relation between pain and plasticity. Anesthesiology 106:864–867
Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769
Woolf CJ, Shortland P, Coggeshall RE (1992) Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 355:75–78
Ziv NE, Garner CC (2004) Cellular and molecular mechanisms of presynaptic assembly. Nat Rev Neurosci 5:385–399
Acknowledgments
This work was supported by the National Natural Sciences Foundation of China (No. 30400421).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, X., Chen, G., Xue, Q. et al. Early Changes of β-Catenins and Menins in Spinal Cord Dorsal Horn after Peripheral Nerve Injury. Cell Mol Neurobiol 30, 885–890 (2010). https://doi.org/10.1007/s10571-010-9517-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-010-9517-9