Elevated nerve growth factor (NGF) in the contralateral dorsal root ganglion (DRG) mediates mirror-image pain after peripheral nerve injury, but the underlying mechanism remains unclear. Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG synapse-like structures made by neurite sprouts of calcitonin gene-related peptide (CGRP+) nociceptors and sympathetic axons onto neurite sprouts of Kv4.3+ nociceptors. These synapse-like structures are formed near NGF-releasing satellite glia surrounding large DRG neurons. Downregulation of the postsynaptic protein PSD95 with a specific shRNA largely eliminates these synapse-like structures, suppresses activities of Kv4.3+ but not CGRP+ nociceptors, and attenuates mirror-image pain. Furthermore, neutralizing the neurotransmitter norepinephrine or CGRP in the synapse-like structures by antibodies has similar analgesic effect. Thus, elevated NGF after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral DRG, leading to the development of chronic mirror-image pain.
Supplemental Digital Content is Available in the Text.Elevated nerve growth factor after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral dorsal root ganglion, leading to the development of chronic mirror-image pain.
aInstitute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei, Taiwan
bDepartment of Medicine, MacKay Medical College, New Taipei City, Taiwan
cDepartment of Anesthesiology, MacKay Memorial Hospital, Taipei, Taiwan
dMacKay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan
Corresponding author. Address: Institute of Neuroscience, National Yang-Ming University, #155, Li-Nong St, Sec. 2, Taipei 112, Taiwan. Tel.: (886) (2) 2826-7153; fax: (886) (2) 2820-0259. E-mail address: firstname.lastname@example.org (M.-L. Tsaur).
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Received March 16, 2015
Received in revised form June 08, 2015
Accepted June 19, 2015