, 2000 and Rozas et al., 2003). Although pain perception cannot be properly considered a disease, persistent or recurrent pain is associated to a number of disorders of distinct origins and pathophysiological bases, including neuropathic pain. Initial support for the involvement of KARs in pain transmission came from the fact that several KAR antagonists possess analgesic activity in a number of animal

models of pain. AT13387 For instance, SYM 2081 increases the latency of escape in the hot plate and chronic constriction injury tests, presumably acting as a functional antagonist (Sutton et al., 1999), whereas the antagonist of GluK1-containing receptors, LY382884, decreases the frequency of paw licking induced by the subcutaneous injection of formalin (Simmons et al., 1998). In keeping with these results, the ablation of Grik1 gene mitigates pain-associated behavior ( Ko et al., 2005; see Bhangoo

and Swanson, 2013 for a review and references therein). Interestingly, the activation of primary afferent sensory fibers produces a kainate receptor-mediated EPSC on the dorsal horn neurons (Li et al., 1999). As in the CNS, these synaptic responses are characterized by slow onset and decay time constants. A remarkable feature of these KAR-mediated EPSCs is that they can only be elicited upon nerve stimulation at intensities strong enough to activate the high-threshold Aδ and C fibers. This feature raises the possibility that KARs may be exclusively involved in

nociceptive transmission BMS-354825 mw at this level, a hypothesis that received significant support when opiate agonists were shown to reduce the amplitude of the KAR-mediated EPSC in dorsal horn neurons (Li et al., 1999). In addition, this receptor subtype is also expressed by trigeminal neurons (Sahara et al., 1997) and KARs are generally expressed along nociceptive pathways, from DRG neurons to the cortex (see Wu et al., 2007 for a review). The Oxalosuccinic acid strong indications that GluK1 antagonists modulate pain perception have led to several clinical trials to validate KARs as therapeutic targets for pain treatment (reviewed by Bhangoo and Swanson, 2013). While some of these demonstrated certain efficacy, and positive results were reported in phases I and II for migraine, postoperative pain, and analogous cases, these therapeutic trials appear to have been abandoned (see Bhangoo and Swanson, 2013 and references therein). Thus, the genetic linkage of KAR subunits to diseases are extremely illustrative as to the diseases that may be influenced or triggered by KARs, represent promising lines for further studies into their mechanistic causes. However, much work remains to be done before definitive conclusions can be drawn regarding the exact roles of KARs in brain disease.