Evidence for lysophosphatidic acid 1 receptor signaling in the early phase of neuropathic pain mechanisms in experiments using Ki-16425, a lysophosphatidic acid 1 receptor antagonist.
Lysophosphatidic acid is a bioactive lipid mediator with neuronal activities. We previously reported a crucial role for lysophosphatidic acid 1 receptor-mediated signaling in neuropathic pain mechanisms. Intrathecal administration of lysophosphatidic acid (1 nmol) induced abnormal pain behaviors, such as thermal hyperalgesia, mechanical allodynia, A-fiber hypersensitization, and C-fiber hyposensitization, all of which were also observed in partial sciatic nerve injury-induced neuropathic pain. Ki-16425 (30 mg/kg, i.p.), a lysophosphatidic acid 1 receptor antagonist, completely blocked lysophosphatidic acid-induced neuropathic pain-like behaviors, when administered 30 min but not 90 min before lysophosphatidic acid injection, suggesting that Ki-16425 is a short-lived inhibitor. The blockade of nerve injury-induced neuropathic pain by Ki-16425 was maximum as late as 3 h after the injury but not after this critical period. The administration of Ki-16425 at 3 h but not at 6 h after injury also blocked neurochemical changes, including up-regulation of voltage-gated calcium channel alpha(2)delta-1 subunit expression in dorsal root ganglion and reduction of substance P expression in the spinal dorsal horn. All of these results using Ki-16425 suggest that lysophosphatidic acid 1 receptor-mediated signaling which underlies the development of neuropathic pain works at an early stage of the critical period after nerve injury.
Ma
Lin
L
Nagasaki University Graduate School of Biomedical Sciences, Japan.
Matsumoto
Misaki
M
Xie
Weijiao
W
Inoue
Makoto
M
Ueda
Hiroshi
H
D000818:Animals; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D007555:Isoxazoles; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid