Inhibiting BDNF/TrkB receptor improves resiniferatoxin-induced postherpetic neuralgia through decreasing ASIC3 signaling in dorsal root ganglia

Abstract Background Postherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. Tropomyosin receptor kinase B (TrkB), an endogenous high-affinity receptor of BDNF is abundantly expressed in primary sensory neurons. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB during PHN is unclear. This study aimed to investigate whether BDNF/TrkB contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs). Methods Resiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by measuring the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB/ASIC3 signaling inhibition on the behavioral test, neuronal excitability and inflammatory response in rat models of PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells. Results RTX resulted in significant mechanical allodynia, upregulated the protein expression of BDNF, TrkB, ASIC3, TRAF6, nNOS and c-Fos, and increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the above-mentioned effects of RTX, except for BDNF and TrkB protein expression. In addition, inhibition of TrkB blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling and hyperexcitability of neurons. RTX-induced activation of BDNF was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level and enhanced IL-6, IL-1β, TNF-α level in PC-12 cells, which was blocked by shRNA-ASIC3 transfection. Conclusion These findings demonstrate that inhibiting BDNF/TrkB reduced inflammation, decreased neuronal hyperexcitability and improved mechanical allodynia through regulating ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.