Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury.
Hypersensitivity to mechanical stimulation is a well documented symptom of neuropathic pain, for which there is currently no effective therapy. Src-family kinases (SFKs) are involved in proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here we show that activation of SFKs induced in spinal cord microglia is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in SFK phosphorylation in the ipsilateral dorsal horn, and SFKs were activated in hyperactive microglia but not in neurons or astrocytes. Intrathecal administration of the Src-family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) suppressed nerve injury-induced mechanical hypersensitivity but not heat and cold hypersensitivity. Furthermore, PP2 reversed the activation of extracellular signal-regulated protein kinase (ERK), but not p38 mitogen-activated protein kinase, in spinal microglia. In contrast, there was no change in SFK phosphorylation in primary sensory neurons, and PP2 did not decrease the induction of transient receptor potential ion channel TRPV1 and TRPA1 in sensory neurons. Together, these results demonstrate that SFK activation in spinal microglia contributes to the development of mechanical hypersensitivity through the ERK pathway. Therefore, preventing the activation of the Src/ERK signaling cascade in microglia might provide a fruitful strategy for treating neuropathic pain.
Katsura
Hirokazu
H
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Obata
Koichi
K
Mizushima
Toshiyuki
T
Sakurai
Jun
J
Kobayashi
Kimiko
K
Yamanaka
Hiroki
H
Dai
Yi
Y
Fukuoka
Tetsuo
T
Sakagami
Masafumi
M
Noguchi
Koichi
K
D000818:Animals; D017487:Ankyrins; D015220:Calcium Channels / Q000378:metabolism; D003080:Cold Temperature; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology* / Q000503:physiopathology; D008161:Lumbosacral Region; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000201:enzymology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000201:enzymology*; D013127:Spinal Nerves / Q000293:injuries; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels / Q000378:metabolism; D020196:Trauma, Nervous System / Q000150:complications* / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017487:Ankyrins; D015220:Calcium Channels; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases