piperidines 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

Paclitaxel, which is widely used for the treatment of solid tumors, causes neuropathic pain via poorly understood mechanisms. Previously, we have demonstrated that lysophosphatidic acid (LPA) and its receptors (LPA1 and LPA3) are required for the initiation of peripheral nerve injury-induced neuropathic pain. The present study aimed to clarify whether LPA and its receptors could mediate paclitaxel-induced neuropathic pain.. Intraperitoneal administration of paclitaxel triggered a marked increase in production of LPA species (18:1-, 16:0-, and 18:0-LPA) in the spinal dorsal horn. Also, we found significant activations of spinal cytosolic phospholipase A2 and calcium-independent phospholipase A2 after the paclitaxel treatment. The paclitaxel-induced LPA production was completely abolished not only by intrathecal pretreatment with neurokinin 1 (NK1) or N-methyl-D-aspartate (NMDA) receptor antagonist, but also in LPA1 receptor-deficient (Lpar1-/-) and LPA3 receptor-deficient (Lpar3-/-) mice. In addition, the pharmacological blockade of NK1 or NMDA receptor prevented a reduction in the paw withdrawal threshold against mechanical stimulation after paclitaxel treatments. Importantly, the paclitaxel-induced mechanical allodynia was absent in Lpar1-/- and Lpar3-/- mice.. These results suggest that LPA1 and LPA3 receptors-mediated amplification of spinal LPA production is required for the development of paclitaxel-induced neuropathic pain.

Topics: Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Dizocilpine Maleate; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuralgia; Paclitaxel; Pain Measurement; Phospholipases A2; Piperidines; Receptors, Lysophosphatidic Acid; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spinal Cord Dorsal Horn; Time Factors