title: Modulation of Nav1.8 by Lysophosphatidic Acid in the Induction of Bone Cancer Pain.
abstract: Given that lysophosphatidic acid (LPA) and the tetrodotoxin-resistant sodium channel Nav1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA1 (also known as EDG2) and Nav1.8 in the dorsal root ganglion (DRG) contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in naïve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Nav1.8 expression in L4-6 DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Nav1.8 expression in ipsilateral L4-6 DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Nav1.8 and LPA remarkably enhanced Nav1.8 currents in DRG neurons, and this was blocked by either a protein kinase C (PKC) inhibitor or a PKCε inhibitor. Overall, we demonstrated the modulation of Nav1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.
authors.affiliation: Center for Neuropsychiatric Diseases, Institute of Life Science, Nanchang University, Nanchang, 330031, China. panhaili@ncu.edu.cn.
authors.forename: Hai-Li
authors.initials: HL
authors.lastname: Pan
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Ben-Long
authors.initials: BL
authors.lastname: Liu
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001703:Biophysics; D001859:Bone Neoplasms / Q000150:complications*; D000072716:Cancer Pain / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000150:complications*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006930:Hyperalgesia / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism
chemical_list: C574551:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonylamino)-3-methyl-5-isoxazolyl)benzylsulfanyl)propanoic acid methyl ester; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008246:Lysophospholipids; D062559:NAV1.8 Voltage-Gated Sodium Channel; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; C568319:Scn10a protein, rat; C032881:lysophosphatidic acid
keywords: Bone cancer pain; Dorsal root ganglion; Lysophosphatidic acid; Tetrodotoxin-resistant sodium channel Nav1.8