Mirror-image pain is mediated by nerve growth factor produced from tumor necrosis factor alpha-activated satellite glia after peripheral nerve injury.
Mirror-image pain is characterized by mechanical hypersensitivity on the uninjured mirror-image side. Recent reports favor central mechanisms, but whether peripheral mechanisms are involved remains unclear. We used unilateral spinal nerve ligation (SNL) to induce mirror-image pain in rats. On the mirror-image (contralateral) side, we found that satellite glia in the dorsal root ganglion (DRG) were activated, whereas macrophages/Schwann cells in the DRG and astrocytes/oligodendrocytes/microglia in the dorsal spinal cord were not. Subsequently, an increase in nerve growth factor (NGF) was detected in the contralateral DRG, and NGF immunoreactivity was concentrated in activated satellite glia. These phenomena were abolished if fluorocitrate (a glial inhibitor) was intrathecally injected before SNL. Electrophysiological recordings in cultured small DRG neurons showed that exogenous NGF enhanced nociceptor excitability. Intrathecal injection of NGF into naive rats induced long-lasting mechanical hypersensitivity, similar to SNL-evoked mirror-image pain. Anti-NGF effectively relieved SNL-evoked mirror-image pain. In the contralateral DRG, the SNL-evoked tumor necrosis factor alpha (TNF-α) increase, which started later than in the ipsilateral DRG and cerebrospinal fluid, occurred earlier than satellite glial activation and the NGF increase. Intrathecal injection of TNF-α into naive rats not only activated satellite glia to produce extra NGF in the DRG but also evoked mechanical hypersensitivity, which could be attenuated by anti-NGF injection. These results suggest that after SNL, satellite glia in the contralateral DRG are activated by TNF-α that diffuses from the injured side via cerebrospinal fluid, which then activates satellite glia to produce extra NGF to enhance nociceptor excitability, which induces mirror-image pain.
Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan Department of Anesthesiology, Mackay Memorial Hospital, Mackay Junior College of Medicine, Nursing and Management, and Department of Medicine, Mackay Medical College, Taipei, Taiwan Department of Neurosurgery, Taipei City Hospital Zhongxing Branch, Taipei 103, Taiwan.
Chau-Fu
CF
Cheng
Jen-Kun
JK
Cheng
Chih-Yang
CY
Chen
Cheng-Chang
CC
Lien
Dachen
D
Chu
Szu-Yi
SY
Wang
Meei-Ling
ML
Tsaur
D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism*; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor
Contralateral pain; Dorsal root ganglion; Glial inhibitor; Mechanical hypersensitivity; Neurotrophic factors; Nociceptor excitability; Spinal nerve ligation