geranylgeranyl-pyrophosphate and lysophosphatidic-acid

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE

Topics: Analgesics; Animals; Benzoxazoles; Cells, Cultured; Cyclic AMP; Female; Hyperalgesia; Inflammation; Injections, Spinal; Isoquinolines; Lysophospholipids; Male; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Pain; Pain Threshold; Piperidines; Polyisoprenyl Phosphates; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Lysophosphatidic Acid