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

Pain. 2015 Nov;156(11):2295-2309. doi: 10.1097/j.pain.0000000000000280.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Functional Laterality / physiology*
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism*
  • Gene Expression Regulation / physiology
  • Hyperalgesia / etiology
  • Hyperalgesia / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Nerve Growth Factor / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Neuralgia / complications
  • Neuralgia / metabolism*
  • Neuralgia / pathology*
  • Neurites / pathology
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Shal Potassium Channels / genetics
  • Shal Potassium Channels / metabolism
  • Spinal Puncture
  • Transfection
  • Tyrosine 3-Monooxygenase / metabolism


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Shal Potassium Channels
  • Nerve Growth Factor
  • Tyrosine 3-Monooxygenase