Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model.
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two major members of the neurotrophin family. Using immunohistochemistry and 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 immunoreactivity 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 contralateral DRG from the third to 28th day after ligation. A significantly greater number of BDNF-immunoreactive neurons were observed in the ipsilateral L4 DRG than contralateral side 14 d after ligation. To test the contribution of BDNF to the thermal hyperalgesia produced in this model, we intrathecally injected anti-BDNF antibody at third day after ligation. This treatment clearly attenuated thermal hyperalgesia for a few hours. Almost all BDNF mRNA-expressing neurons coexpressed trkA, a high-affinity NGF receptor, mRNA. The percentage of BDNF mRNA-expressing cells of trkA cells significantly 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 ipsilateral 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 was observed in the ipsilateral L5 DRG and sciatic nerve, but not in the ipsilateral L4 DRG or L4 spinal nerve. Local application of anti-NGF antibody to the L4 spinal nerve beside the L5 spinal nerve-ligation site prevented the development of thermal hyperalgesia for 5 d after ligation. Our data suggest that BDNF, which increased in the uninjured L4 DRG neurons, acts as a sensory neuromodulator in the dorsal horn and contributes to thermal hyperalgesia in this neuropathic pain model. The contribution of locally synthesized NGF to thermal hyperalgesia was also demonstrated. These dynamic alterations in the expression and content of BDNF and NGF in the uninjured DRG neurons might be involved in the pathomechanisms of neuropathic pain.
Fukuoka
T
T
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. tfukuoka@hyo-med.ac.jp
Kondo
E
E
Dai
Y
Y
Hashimoto
N
N
Noguchi
K
K
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D006614:Hindlimb / Q000503:physiopathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007278:Injections, Spinal; D008026:Ligation; D008161:Lumbosacral Region; D008297:Male; D020422:Mononeuropathies / Q000150:complications / Q000503:physiopathology*; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D013127:Spinal Nerves / Q000503:physiopathology*
D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D020917:Receptor, trkA