title: Pharmacological characterization of lysophosphatidic acid-induced pain with clinically relevant neuropathic pain drugs.
abstract: Lysophosphatidic acid (LPA), an initiator of neuropathic pain, causes allodynia. However, few studies have evaluated the pharmacological profile of LPA-induced pain. In this study, a LPA-induced pain model was developed and pharmacologically characterized with clinically relevant drugs used for neuropathic pain, including antiepileptics, non-steroidal anti-inflammatory agents, analgesics, local anaesthetics/antiarrhythmics and antidepressants. Gabapentin (1-30 mg/kg, p.o.) significantly reversed LPA-induced allodynia, but neither indomethacin (30 mg/kg, p.o.) nor morphine (0.3-3 mg/kg, s.c.) did, which indicates that LPA-induced pain consists mostly of neuropathic rather than inflammatory pain. Both pregabalin (0.3-10 mg/kg, p.o.) and ω-CgTX MVIIA (0.01-0.03 μg/mouse, i.t.) completely reversed LPA-induced allodynia in a dose-dependent manner. Lidocaine (1-30 mg/kg, s.c.), mexiletine (1-30 mg/kg, p.o.) and carbamazepine (10-100 mg/kg, p.o.) significantly ameliorated LPA-induced allodynia dose dependently. Milnacipran (30 mg/kg, i.p.) produced no significant analgesic effect in LPA-induced allodynia. In LPA-injected mice, expression of the α2δ1 subunit of the voltage-gated calcium channel (VGCC) was increased in the dorsal root ganglion (DRG) and spinal dorsal horn. Furthermore, the VGCC current was potentiated in both the DRG from LPA-injected mice and LPA (1 μM)-treated DRG from saline-injected mice, and the potentiated VGCC current was amended by treatment with gabapentin (100 μM). The LPA-induced pain model described here mimics aspects of the neuropathic pain state, including the sensitization of VGCC, and may be useful for the early assessment of drug candidates to treat neuropathic pain.
authors.affiliation: Pain and Neurology, Discovery Research Laboratories, Shionogi & Co., Ltd, Shiga, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Takasu
authors.forename: S
authors.initials: S
authors.lastname: Shinohara
authors.forename: Y
authors.initials: Y
authors.lastname: Yoneda
authors.forename: A
authors.initials: A
authors.lastname: Kato
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D008246:Lysophospholipids; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000069583:Pregabalin; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000588:Amines; D000700:Analgesics; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D008246:Lysophospholipids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine; C032881:lysophosphatidic acid; D007213:Indomethacin