TY - JOUR T1 - Antiallodynic and Antihyperalgesic Effects of Selective Competitive GLU<sub>K5</sub> (GluR5) Ionotropic Glutamate Receptor Antagonists in the Capsaicin and Carrageenan Models in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 396 LP - 404 DO - 10.1124/jpet.106.105601 VL - 319 IS - 1 AU - Carrie K. Jones AU - Andrew Alt AU - Ann Marie Ogden AU - David Bleakman AU - Rosa M. A. Simmons AU - Smriti Iyengar AU - Esteban Dominguez AU - Paul L. Ornstein AU - Harlan E. Shannon Y1 - 2006/10/01 UR - http://jpet.aspetjournals.org/content/319/1/396.abstract N2 - GLUK5 kainate receptor subunits are abundant in pain pathways, including dorsal root ganglia and spinothalamic neurons, as well as in the thalamus and brain stem. A growing body of evidence indicates that the GLUK5 kainate receptor subtype plays a prominent role in pain transmission, particularly in persistent pain. In the present studies, compounds from a novel series of amino acid GLUK5 receptor antagonists were evaluated for their effectiveness in reversing capsaicin-induced mechanical allodynia as well as carrageenan-induced thermal hyperalgesia. In vitro, the amino acid compounds were efficacious in blocking glutamate-evoked calcium flux in cells expressing GLUK5 but not GLUK6 or GLUA2, homomeric receptors. Electrophysiologically, the compounds exhibited selectivity for kainate receptors in dorsal root ganglion cells relative to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide and N-methyl-d-aspartate receptors in hippocampal pyramidal neurons. The amino acid compounds were poorly efficacious in the pain tests after s.c. or p.o. administration. However, compounds were highly efficacious after central intracisternal administration, and the rank order of potencies correlated with their rank order of affinities at GLUK5 receptors determined in vitro, indicating that the lack of activity after systemic administration was due to poor oral bioavailability. To increase oral bioavailability, isobutyl or 2-ethylbutyl ester prodrugs of the parent amino acids were prepared. The prodrugs, which produced robust plasma levels of parent amino acids, were highly efficacious in the capsaicin and carrageenan tests. The present studies provide further evidence that selective GluK5 kainate receptor subtype antagonists can reverse allodynia and hyperalgesia, particularly in persistent pain states. The American Society for Pharmacology and Experimental Therapeutics ER -