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Nerve growth factor–induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain

Cheng, Chau-Fua; Cheng, Jen-Kunb,c,d; Chen, Chih-Yanga; Rau, Ruey-Horngc; Chang, Yu-Chenga; Tsaur, Meei-Linga,*

doi: 10.1097/j.pain.0000000000000280
Research Paper
Global Year

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: mltsaur@ym.edu.tw (M.-L. Tsaur).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received March 16, 2015

Received in revised form June 08, 2015

Accepted June 19, 2015

© 2015 International Association for the Study of Pain
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