Profiling of BoNT/C3-reversible gene expression induced by lysophosphatidic acid: ephrinB1 gene up-regulation underlying neuropathic hyperalgesia and allodynia.
Lysophosphatidic acid (LPA) signaling, through LPA(1) receptor and its downstream RhoA, has been reported to initiate nerve injury-induced neuropathic pain. In the present study, we performed gene expression profiling of the dorsal root ganglion (DRG) to identify genes induced by intrathecal injection of LPA in a botulinum toxin C3 (BoNT/C3)-reversible manner. We selected and functionally characterized ephrinB1 from 82 identified genes as a potential gene involved in pain transmission, since ephrinB1 is implicated to modulate N-methyl-d-aspartate (NMDA) receptor functions in spinal pain transmission. The LPA-induced and BoNT/C3-reversible ephrinB1 gene expression was confirmed by quantitative real-time PCR. Furthermore, treatments with an antisense oligodeoxynucleotide for ephrinB1 largely abolished the LPA-induced thermal hyperalgesia and allodynia in response to mechanical or Abeta-fiber-mediated electrical stimuli on day 1 after the injection. In addition, intrathecal treatment with a soluble ligand, ephrinB1-Fc, caused similar neuropathic pain-like behaviors in a manner that was reversible by the NMDA receptor antagonist MK-801. These results suggest that ephrinB1 plays a crucial role in LPA-induced neuropathic pain. In addition, the present study may provide a new strategy to identify unique neuropathic pain-related genes.
Uchida
Hitoshi
H
Nagasaki University Graduate School of Biomedical Sciences, Bunkyo-machi, Japan.
Matsumoto
Misaki
M
Ueda
Hiroshi
H
D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D004558:Electric Stimulation / Q000009:adverse effects; D036387:Ephrin-B1 / Q000235:genetics*; D036342:Ephrins / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D036387:Ephrin-B1; D036342:Ephrins; D018691:Excitatory Amino Acid Antagonists; D008246:Lysophospholipids; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D001905:Botulinum Toxins; C096324:botulinum toxin type C; C032881:lysophosphatidic acid