Peripheral injury or disease induced alterations in

Peripheral injury- or disease-induced alterations in synaptic efficacy occur not only at the first synapse made by the primary nociceptive afferents in the spinal dorsal horn but are also operational in several regions processing the sensorimotor as well as emotional-affective components of pain, such as the thalamus, somatosensory cortex, cingulate cortex, brain stem nuclei, and PAG Gebhart 2004, Johansen et al. 2001, Tinazzi et al. 2000 as well as in limbic structures such as the hippocampus (Vaccarino and Melzack, 1992) and amygdala, where AMPA receptor subunits are expressed Tolle et al. 1993, Geiger et al. 1995, Petralia et al. 1997. Both short-term and long-term plastic changes in cortical glutamatergic synaptic transmission occur in the cortex in animal models of pathological pain (Johansen et al., 2001) and in humans (Flor, 2002). Interestingly, mice demonstrated a specific reduction in activity-induced Fos upregulation associated with a sensitization of noxious inputs in the hindlimb somatosensory cortex as well as in the anterior cingulate cortex, a region responsible for emotional learning and for encoding the affective “aversiveness” to nociceptor stimulation (Johansen et al., 2001), although cortical responsiveness to acute noxious stimulation was not affected. These data suggest that GluR-A-containing AMPA receptors could contribute to pain-related plasticity in cortical regions involved in the perception, memory, and emotional modulation of pain and provide a basis for testing these hypotheses in region-specific, conditional GluR-deficient mice.
Experimental Procedures
Acknowledgements
Introduction α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic jlk (AMPA) receptors form a subclass of ionotropic glutamate receptors that are abundantly distributed throughout the brain (reviewed in Ozawa et al., 1998). They mediate excitatory currents during fast synaptic neurotransmission in most neurons of the brain. AMPA receptors also have an important role in learning and memory because their synaptic cell membrane expression is very plastic, as their membrane trafficking can be altered rapidly, for example, in long-term potentiation and depression (Citri and Malenka, 2008). Native AMPA receptors are heterotetramers that are composed of GluR-A–D (GluR1-4; GluA1-4) subunits (Keinänen et al., 1990, Rosenmund et al., 1998). In heterologous expression systems, all AMPA receptor subunits can form functional receptors as homomers. Ethanol inhibits the function of ionotropic glutamate receptors (Dildy-Mayfield and Harris, 1992, Lovinger, 1993, Lovinger et al., 1990). N-methyl-d-aspartate (NMDA) receptors are considered to be the most important target among the glutamate receptors in acute actions of ethanol. NMDA receptors are inhibited by ethanol in synaptic transmission in brain slices, the threshold concentration being around 1–10mM (Lovinger et al., 1990). Most of the published studies indicate that AMPA receptor–mediated excitatory postsynaptic currents are not markedly inhibited by ethanol in brain-slice preparations when the currents are evoked by electrical stimulation of afferent axons (e.g., Lovinger et al., 1990). To date, AMPA receptors activated by presynaptically released glutamate have been shown to be inhibited only in the central amygdala and in the CA3 area of hippocampus of neonatal rats (Mameli et al., 2005, Zhu et al., 2007). In some experiments carried out using individual neurons or heterologously expressed recombinant receptors, both glutamate receptor subclasses have been reported to be similarly sensitive to ethanol (Dildy-Mayfield and Harris, 1992, Wirkner et al., 2000). In those studies, the agonist is applied over a relatively long time period that produces desensitization of a substantial fraction of ion channels. Our previous study provided evidence that ethanol inhibition of AMPA receptors is strongly enhanced by receptor desensitization (Möykkynen et al., 2003).