T. Fukuoka et al., Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model, J NEUROSC, 21(13), 2001, pp. 4891-4900
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are
two major members of the neurotrophin family. Using immunohistochemistry an
d in situ hybridization histochemistry, we examined the effect of L5 spinal
nerve ligation (SPNL), a neuropathic pain model, on the expression of BDNF
in the uninjured L4 dorsal root ganglion (DRG). After L5 SPNL, both immuno
reactivity for BDNF and the hybridization intensity for BDNF mRNA increased
mainly in the small- and medium-sized neurons. The percentage of BDNF mRNA
-expressing neurons increased in the ipsilateral L4 DRG compared with the c
ontralateral DRG from the third to 28th day after ligation. A significantly
greater number of BDNF-immunoreactive neurons were observed in the ipsilat
eral L4 DRG than contralateral side 14 d after ligation. To test the contri
bution of BDNF to the thermal hyperalgesia produced in this model, we intra
thecally injected anti-BDNF antibody at third day after ligation. This trea
tment clearly attenuated thermal hyperalgesia for a few hours. Almost all B
DNF mRNA-expressing neurons coexpressed trkA, a high-affinity NGF receptor,
mRNA. The percentage of BDNF mRNA-expressing cells of trkA cells significa
ntly increased in the ipsilateral L4 DRG 14 d after ligation. Furthermore,
we examined the contribution of NGF on this phenotypic change using ELISA,
Northern blot analysis, and anti-NGF antibody. NGF content in the ipsilater
al L4 DRG linearly increased and reached a statistical significant level 14
d after L5 SPNL. Moreover, at this time point, the increase in NGF mRNA wa
s observed in the ipsilateral L5 DRG and sciatic nerve, but not in the ipsi
lateral L4 DRG or L4 spinal nerve. Local application of anti-NGF antibody t
o the L4 spinal nerve beside the L5 spinal nerve-ligation site prevented th
e development of thermal hyperalgesia for 5 d after ligation. Our data sugg
est that BDNF, which increased in the uninjured L4 DRG neurons, acts as a s
ensory neuromodulator in the dorsal horn and contributes to thermal hyperal
gesia in this neuropathic pain model. The contribution of locally synthesiz
ed NGF to thermal hyperalgesia was also demonstrated. These dynamic alterat
ions in the expression and content of BDNF and NGF in the uninjured DRG neu
rons might be involved in the pathomechanisms of neuropathic pain.