Ionotropic glutamate receptors contain three subtypes: NMDA, AMPA and kainate receptors. The former two receptor subtypes have well defined roles in nociception, while the role of kainate receptors in pain is not as well characterized. Kainate receptors are expressed in nociceptive pathways, including the dorsal root ganglion, spinal cord, thalamus and cortex. Electrophysiological studies show that functional kainate receptors are located postsynaptically, where they mediate a portion of

more »

... ory synaptic transmission, or are located presynaptically, where they modulate excitatory or inhibitory neurotransmission. Recent genetic and pharmacological studies suggest that kainate receptors can regulate nociceptive responses. These results highlight kainate receptors as a target for the development of new treatments for chronic pain. utilize genetic and pharmacological tools to dissect the role of KA receptors in pain transmission. Finally, based on current results from animal and human studies, we will discuss how KA receptors may serve as a potential target for the development of new therapies designed for the treatment of chronic pain. KAINATE RECEPTORS: DIVERSITY, STRUCTURE AND SYNAPTIC FUNCTION KA receptors are one of three subtypes of ionotropic receptors for glutamate and are composed of five different subunits: GluR5, GluR6, GluR7, KA1 and KA2 [13] . Similar to AMPA and NMDA receptors, KA receptors are thought to exist as tetramers. Each subunit of KA receptors contains four hydrophobic domains M1-4, with the NH2-terminal domain lying extracellularly and the COOH-terminal intracellularly. Among these hydrophobic domains, M1, 3 and 4 cross the membrane while the M2 domain forms a hairpinlike loop in the membrane comprising the pore-forming domain [14] [15] [16] . While GluR5-7 homomers are functional, KA1 and KA2 can not produce functional homomeric channels, although they are functional in combination with . Interestingly, GluR5-7 can also coassemble to form heteromers [18] [19] [20] . The diversity of KA receptors is increased by the existence of splice variants for GluR5 (GluR5a, 5b and 5c), GluR6 (GluR6a and 6b) and GluR7 receptor subunits (GluR7a and 7b) [21, 22] . With the development of KA receptor specific drugs and knockout mice, studies have defined the functional roles of KA receptors in both mediating and modulating synaptic transmission and synaptic plasticity [9, 10, 23]. Postsynaptic KA receptors that mediate excitatory synaptic transmission were initially found at hippocampal mossy fiber synapses by repetitive stimulation [24, 25] and in spinal cord slices using a single stimulation [26] . A number of studies have reported KA receptor-mediated synaptic responses in other central