Novel analgesics targeting brain-derived neurotrophic factor for neuropathic pain
Brain-derived neurotrophic factor (BDNF) is necessary for the development, growth, and maintenance of nerve cells. BDNF is expressed in the dorsal root ganglion (DRG); binds to the Tropomyosin receptor kinasa B (TrkB) receptor, which has a tyrosine kinase domain, in the spinal cord; and plays an important role as a pain modulator. BDNF expression is increased in various types of pain, including acute pain, neuropathic pain, and cancer pain. Activation of the BDNF–TrkB pathway transmits pain information. In order to inhibit the BDNF–TrkB pathway, by sequestering BDNF, we constructed a cDNA expression plasmid encoding the extracellular region of rat TrkB fused to enhanced green fluorescent protein (EGFP). When the expression plasmid vector was administered to rat models of neuropathic pain, induced by spinal nerve ligation, statistically significant relief of pain was observed in terms of a 50% paw-withdrawal threshold using the von Frey test. The expression of TrkB-EGFP mRNA was detected in L5 lumbar vertebral nerves by quantitative reverse transcriptase polymerase chain reaction. To verify the pain-suppressive effect of the expression vector, truncated TrkB protein, without EGFP, was purified, and administered to pain model rats. A statistically significant suppressive effect of the truncated TrkB protein on neuropathic pain was observed 2 days after administration. The pain-suppressive effect of the truncated TrkB protein was more effective than that of the TrkB-Fc chimera protein and lasted longer than that of the TrkB antagonist ANA-12. Our results suggested that the truncated TrkB cDNA expression vector and truncated TrkB protein could be used as molecular targeted drugs in patients with neuropathic pain.