Paul Ornstein - Antiallodynic and antihyperalgesic effects of selective competitive GLUK5 (GluR5) ionotropic glutamate receptor antagonists in the capsaicin and carrageenan models in rats.

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  Jones, Carrie K, Alt, Andrew, Ogden, Ann Marie, Bleakman, David,   Simmons, Rosa M A, Iyengar, Smriti, Dominguez, Esteban, Ornstein,   Paul L, Shannon, Harlan E The Journal Of Pharmacology And   Experimental Therapeutics 2006 319  (1) 396-404

  Abstract: GLU(K5) 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 GLU(K5) 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 GLU(K5) 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 GLU(K5) but not GLU(K6) or   GLU(A2), homomeric receptors. Electrophysiologically, the   compounds exhibited selectivity for kainate receptors in dorsal   root ganglion cells relative to   alpha-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 GLU(K5)   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-ethyl-butyl 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 Glu(K5) kainate receptor subtype antagonists can   reverse allodynia and hyperalgesia, particularly in persistent   pain states.;

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