Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice.
Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were completely suppressed by repeated intrathecal (i.t.) injection of a TrkB/Fc chimera protein, which sequesters endogenous brain-derived neurotrophic factor (BDNF). In addition, BDNF heterozygous (+/-) knockout mice exhibited a significant suppression of nerve ligation-induced thermal hyperalgesia and tactile allodynia compared with wild-type mice. After nerve ligation, BDNF-like immunoreactivity on the superficial laminae of the ipsilateral side of the spinal dorsal horn was clearly increased compared with that of the contralateral side. It should be noted that a single i.t. injection of BDNF produced a long-lasting thermal hyperalgesia and tactile allodynia in normal mice, and these responses were abolished by i.t. pre-treatment with either a Trk-dependent tyrosine kinase inhibitor K-252a or a selective protein kinase C (PKC) inhibitor Ro-32-0432. Supporting these findings, we demonstrated here for the first time that the increase in intracellular Ca2+ concentration by application of BDNF in cultured mouse spinal neurons was abolished by pre-treatment with either K-252a or Ro-32-0432. Taken together, these findings suggest that the binding of spinally released BDNF to TrkB by nerve ligation may activate PKC within the spinal cord, resulting in the development of a neuropathic pain-like state in mice.
Yajima
Yoshinori
Y
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
Narita
Minoru
M
Usui
Aiko
A
Kaneko
Chihiro
C
Miyatake
Mayumi
M
Narita
Michiko
M
Yamaguchi
Takanori
T
Tamaki
Hiroko
H
Wachi
Hiroshi
H
Seyama
Yoshiyuki
Y
Suzuki
Tsutomu
T
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods*; D013116:Spinal Cord / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor