So far the functional significance

So far, the functional significance of GluR-A and GluR-B in synaptic plasticity has been best studied in the context of long-term potentiation of synaptic transmission in vitro in the hippocampus and the regulation of synaptic strength in paradigms underlying activity-dependent learning in vivo Takahashi et al. 2003, Jia et al. 1996, Zamanillo et al. 1999, Reisel et al. 2002. Recent evidence suggests that the molecular and cellular mechanisms involved in cognitive and emotional learning are also operational in leaving memory traces in pain pathways, which become manifest as nociceptive hypersensitivity and chronic pain Ikeda et al. 2003, Sandkühler 2000, Flor 2002. Interestingly, analogous to a requirement for GluR-A in hippocampal LTP (Zamanillo et al., 1999), we observe that the GluR-A subunit is required for a rapid sensitization in the spinal dorsal horn. Furthermore, consistent with a role for GluR-A in short-term spatial memory, but not in long-term memory consolidation (Reisel et al., 2002), we observe selective deficits in GluR-A knockout mice in paradigms of early, but not long-lasting, nociceptive hypersensitivity. Conversely, GluR-B knockout mice are known to demonstrate enhanced hippocampal LTP (Jia et al., 1996), and we show here that they develop exaggerated sensitization in paradigms of short-term as well as long-term nociceptive hypersensitivity. Thus, our experiments with the GluR mutant mice consolidate the emerging view that sensitization phenomena in the spinal dorsal horn share common molecular mechanisms with hippocampal LTP Willis 1997, Sandkühler 2002. Furthermore, our data predict that a lack of GluR-B-containing AMPA receptors (or a corresponding enrichment of GluR-A-containing AMPA receptors) would lead to long-lasting nociceptive hypersensitivity in pathological states. When could such circumstances arise and how would they modulate synaptic AMPA receptors? First, peripheral injury could change spinal AMPA Genipin composition via transcriptional regulation of GluR genes, as reported in inflammatory pain models (Zhou et al., 2001). Second, along the lines of rapid alterations in the composition of synaptic AMPA receptors induced by activity in the cerebellum (Liu and Cull-Candy, 2000), hippocampus (Shi et al., 2001), and the cortex (Takahashi et al., 2003), persistent activation of primary nociceptive afferent fibers could rapidly regulate synaptic AMPA receptor composition on spinal neurons. This can be achieved by modulating the phosphorylation status of GluR-A and GluR-B subunits and their binding to PDZ domain-containing synaptic scaffolding proteins, thereby changing membrane targeting and synaptic availability of AMPA receptors Malinow and Malenka 2002, Takahashi et al. 2003. Interestingly, recent studies report changes in the phosphorylation status of GluR-A in the spinal dorsal horn in postinflammatory states Fang et al. 2003a, Fang et al. 2003b, Nagy et al. 2004. Furthermore, rapid changes in PDZ domain protein interactions of AMPA receptor subunits in the spinal dorsal horn are associated with serotonin-induced facilitation of spinal synaptic transmission (Li et al., 1999). Third, rapid local dendritic synthesis of GluR subunits could contribute to activity-dependent regulation of AMPA receptor composition at spinal synapses, as demonstrated recently in cultured hipppocampal neurons (Ju et al., 2004). Finally, potential changes in the efficacy of editing of the GluR-B mRNA in disease states could modulate pain pathophysiology by altering AMPA receptor composition in the spinal dorsal horn. Indeed, dysfunctional GluR-B editing has been reported in the spinal cord of humans in neurodegenerative disease states, such as amyotrophic lateral sclerosis (Kawahara et al., 2004), and it remains to be seen whether similar changes occur in patients suffering from chronic inflammatory or neuropathic pain. Thus, it will be very important to direct future studies at these and additional potential molecular mechanisms to fully understand the contribution of spinal AMPA receptors to the development of chronic pain syndromes.