Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain.
Neuropathic pain that occurs after peripheral nerve injury is poorly controlled by current therapies. Increasing evidence shows that mitogen-activated protein kinase (MAPK) play an important role in the induction and maintenance of neuropathic pain. Here we show that activation of extracellular signal-regulated protein kinases 5 (ERK5), also known as big MAPK1, participates in pain hypersensitivity caused by nerve injury. Nerve injury increased ERK5 phosphorylation in spinal microglia and in both damaged and undamaged dorsal root ganglion (DRG) neurons. Antisense knockdown of ERK5 suppressed nerve injury-induced neuropathic pain and decreased microglial activation. Furthermore, inhibition of ERK5 blocked the induction of transient receptor potential channels and brain-derived neurotrophic factor expression in DRG neurons. Our results show that ERK5 activated in spinal microglia and DRG neurons contributes to the development of neuropathic pain. Thus, blocking ERK5 signaling in the spinal cord and primary afferents has potential for preventing pain after nerve damage.
Obata
Koichi
K
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Katsura
Hirokazu
H
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Mizushima
Toshiyuki
T
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Sakurai
Jun
J
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Kobayashi
Kimiko
K
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Yamanaka
Hiroki
H
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Dai
Yi
Y
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Fukuoka
Tetsuo
T
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
Noguchi
Koichi
K
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000473:pathology*; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000201:enzymology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology / Q000473:pathology*; D009475:Neurons, Afferent / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000473:pathology; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors
D002070:Butadienes; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D009570:Nitriles; D016376:Oligonucleotides, Antisense; D050916:TRPV Cation Channels; C113580:U 0126; D048054:Mitogen-Activated Protein Kinase 7