Direct evidence for the involvement of brain‐derived neurotrophic factor in the development of a neuropathic pain‐like state in mice

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Abstract
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.