Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling.
Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.
Inoue
Makoto
M
Division of Molecular Pharmacology and Neuroscience, Nagasaki University, Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan.
Rashid
Md Harunor
MH
Fujita
Ryousuke
R
Contos
James J A
JJ
Chun
Jerold
J
Ueda
Hiroshi
H
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D006930:Hyperalgesia / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000209:etiology*; D011493:Protein Kinase C / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D049368:Receptors, Lysophosphatidic Acid; D015398:Signal Transduction / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; C087857:protein kinase C gamma; D011493:Protein Kinase C; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein