Antiallodynic and Antihyperalgesic Effects of Selective Competitive GLU_(k5)(GluR5)lonotropic Glutamate Receptor Antagonists in the Capsaicin and Carrageenan Models in Rats

摘要

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 hydro-bromide 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 in-tracisternal 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-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 Glu_(K5)kainate receptor subtype antagonists can reverse allodynia and hyperalgesia,particularly in persistent pain states.