Neuron-Derived ADAM10 Production Stimulates Peripheral Nerve Injury-Induced Neuropathic Pain by Cleavage of E-Cadherin in Satellite Glial Cells.
BACKGROUND
Increasing evidence suggests the potential involvement of metalloproteinase family proteins in the pathogenesis of neuropathic pain, although the underlying mechanisms remain elusive.


METHODS
Using the spinal nerve ligation model, we investigated whether ADAM10 proteins participate in pain regulation. By implementing invitro methods, we produced a purified culture of satellite glial cells to study the underlying mechanisms of ADAM10 in regulating neuropathic pain.


RESULTS
Results showed that the ADAM10 protein was expressed in calcitonin gene-related peptide (CGRP)-containing neurons of the dorsal root ganglia, and expression was upregulated following spinal nerve ligation surgery invivo. Intrathecal administration of GI254023X, an ADAM10 selective inhibitor, to the rats one to three days after spinal nerve ligation surgery attenuated the spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia. Intrathecal injection of ADAM10 recombinant protein simulated pain behavior in normal rats to a similar extent as those treated by spinal nerve ligation surgery. These results raised a question about the relative contribution of ADAM10 in pain regulation. Further results showed that ADAM10 might act by cleaving E-cadherin, which is mainly expressed in satellite glial cells. GI254023X reversed spinal nerve ligation-induced downregulation of E-cadherin and activation of cyclooxygenase 2 after spinal nerve ligation. β-catenin, which creates a complex with E-cadherin in the membranes of satellite glial cells, was also downregulated by spinal nerve ligation surgery in satellite glial cells. Finally, knockdown expression of β-catenin by lentiviral infection in purified satellite glial cells increased expression of inducible nitric oxide synthase and cyclooxygenase 2.


CONCLUSIONS
Our findings indicate that neuron-derived ADAM10 production stimulates peripheral nerve injury-induced neuropathic pain by cleaving E-cadherin in satellite glial cells.
Department of Anesthesiology, Neuroscience Research Centre, Changzheng Hospital.
Jian
J
Li
Department of Anesthesiology, Neuroscience Research Centre, Changzheng Hospital.|Eastern Hepatobiliary Surgery Hospital.
Qing
Q
Ouyang
Department of Anesthesiology, 309th Hospital of PLA, Beijing, China.
Cheng-Wen
CW
Chen
Eastern Hepatobiliary Surgery Hospital.
Qian-Bo
QB
Chen
Department of Anesthesiology, Neuroscience Research Centre, Changzheng Hospital.
Xiang-Nan
XN
Li
Department of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Second Military Medical University, Shanghai, China.
Zheng-Hua
ZH
Xiang
Department of Anesthesiology, Neuroscience Research Centre, Changzheng Hospital.
Hong-Bin
HB
Yuan
D000072197:ADAM10 Protein / Q000096:biosynthesis*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027161:Satellite Cells, Perineuronal / Q000378:metabolism*; D013127:Spinal Nerves
C000610228:CDH1 protein, rat; D015820:Cadherins; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat
ADAM10; Dorsal Root Ganglia; E-Cadherin; Neuropathic Pain; Satellite Glia Cell