Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice

Emer M Garry, Andrew Moss, Ada Delaney, Francis O'Neill, James Blakemore, Julian Bowen, Holger Husi, Rory Mitchell, Seth G.N. Grant, Susan M. Fleetwood-Walker

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Chronic pain due to nerve injury is resistant to current analgesics. Animal models of neuropathic pain show neuronal plasticity and behavioral reflex sensitization in the spinal cord that depend on the NMDA receptor. We reveal complexes of NMDA receptors with the multivalent adaptor protein PSD-95 in the dorsal horn of spinal cord and show that PSD-95 plays a key role in neuropathic reflex sensitization. Using mutant mice expressing a truncated form of the PSD-95 molecule, we show their failure to develop the NMDA receptor-dependent hyperalgesia and allodynia seen in the CCI model of neuropathic pain, but normal inflammatory nociceptive behavior following the injection of formalin. In wild-type mice following CCI, CaM kinase II inhibitors attenuate sensitization of behavioral reflexes, elevated constitutive (autophosphorylated) activity of CaM kinase II is detected in spinal cord, and increased amounts of phospho-Thr(286) CaM kinase II coimmunoprecipitate with NMDA receptor NR2A/B subunits. Each of these changes is prevented in PSD-95 mutant mice although CaM kinase II is present and can be activated. Disruption of CaM kinase II docking to the NMDA receptor and activation may be responsible for the lack of neuropathic behavioral reflex sensitization in PSD-95 mutant mice.
Original languageEnglish
Pages (from-to)321-328
Number of pages8
JournalCurrent Biology : CB
Volume13
Issue number4
DOIs
Publication statusPublished - 1 Feb 2003

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    Garry, E. M., Moss, A., Delaney, A., O'Neill, F., Blakemore, J., Bowen, J., Husi, H., Mitchell, R., Grant, S. G. N., & Fleetwood-Walker, S. M. (2003). Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Current Biology : CB, 13(4), 321-328. https://doi.org/10.1016/S0960-9822(03)00084-8