Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 25 February 2003
Vol. 2003, Issue 171, p. tw79
[DOI: 10.1126/stke.2003.171.tw79]

EDITORS' CHOICE

Neurobiology Synaptic Mechanism for Pain Sensitization

Injured spinal nerves, caused by trauma or inflammation, can cause chronic pain that is not blunted by conventional analgesics. Two groups investigated mechanisms underlying this hyperalgesic response. Garry et al. examined the molecular mechanisms that account for sensitization of behavioral reflexes in response to painful stimuli in mice with a chronic constriction injury to the common sciatic nerve. The adaptor protein PSD-95 was localized in spinal cord neurons likely to influence pain sensitivity. In transgenic mice expressing a truncated form of PSD-95, the enhanced sensitivity to pain normally caused by the constriction injury was reduced or absent, whereas a control response to pain caused by inflammation was not altered. One role of PSD-95 is to localize Ca2+-calmodulin-dependent protein kinase II (CaM kinase II) to complexes with N-methyl-D-aspartate (NMDA) receptors. In wild-type mice, pharmacological inhibitors of CaM kinase II also reduced sensitization to pain after injury, and the amount of phosphorylated active CaM kinase II associated with NMDA receptors in spinal neurons was increased after nerve injury. Although the results do not rule out roles for other targets of PSD-95, organization of CaM kinase II in complexes with NMDA receptors appears to be a key aspect of increased sensitivity after neuronal damage. In fact, high concentrations of NMDA still activated CaM kinase II in PSD-95-mutant animals, even though injury-induced activation of the kinase was blocked. Thus, the response to neuronal injury may critically depend on a particular subcellular population of the enzyme, likely that tethered to NMDA receptors through PSD-95. Ikeda et al. analyzed the induction of long-term potentiation (LTP) in neurons of lamina 1 of the spinal cord evoked by pain-transmitting C fibers. Only those neurons that expressed neurokinin 1 receptors, which is activated by substance P, exhibited LTP. Additionally, LTP was blocked if the NMDA receptors were inhibited or if increases in the concentration of intracellular Ca2+ were blocked by inhibition of release from intracellular stores or inhibition of T-type Ca2+ channels. Thus, these two reports address mechanisms underlying the hyperalgesic response to nociceptive stimuli.

E. M. Garry, A. Moss, A. Delaney, F. O'Neill, J. Blakemore, J. Bowen, H. Husi, R. Mitchell, S. G. N. Grant, S. M. Fleetwood-Walker, Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Curr. Biol. 13, 321-328 (2003). [Online Journal]

H. Ikeda, B. Heinke, R. Ruscheweyh, J. Sandkühler, Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299, 1237-1240 (2003). [Abstract] [Full Text]

Citation: Synaptic Mechanism for Pain Sensitization. Sci. STKE 2003, tw79 (2003).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882