Inhibiting BDNF/TrkB.T1 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. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 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 detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced 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 injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation 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, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection. Conclusion These findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.

lncRNA BDNF-AS Attenuates Propofol-Induced Apoptosis in HT22 Cells by Modulating the BDNF/TrkB Pathway

“…Matusica et al [ 21 ] indicated that BDNF enables P75 (NTR)-derived trophic cell permeapeptides (c29) to promote neuronal survival through the TrkB-dependent signaling pathway in vitro and in vivo. The BDNF/TrkB pathway in learning and memory [ 22 ], chronic pain [ 23 ], and retinopathy [ 24 ] has been deeply studied, but there are few studies on neuronal apoptosis. BDNF-AS is a natural antisense transcript that inhibits the transcription of BDNF [ 15 , 25 ].…”

Resting-State Functional Connectivity Analyses: Brain Functional Reorganization in a Rat Model of Postherpetic Neuralgia

“…All rats were randomly divided into two groups, the PHN group ( n = 12) and the control group (Con group, n = 12). The PHN group rats were anesthetized with isoflurane (2% in O 2 ), and then administered a single intraperitoneal injection of RTX (210 ug/kg, LC Laboratories, Woburn, MA), as previously described [ 8 , 9 ]. RTX was dissolved in a mixture of 10% Tween 80 (Sigma, St. Louis, MO, USA) and 10% ethanol in the normal saline [ 18 ].…”

“…The thermal withdrawal latency was measured by inducing the latency of rats’ leg reflex with thermal stimulation, as a thermal pain threshold [ 8 , 9 , 18 ]. After 30 min of adaption, the heat sensitivity was evaluated by a thermal radiation pain meter that exposed the midfoot surface of the hind paw to the light beam on the transparent glass surface.…”

“…There are various theories to explain pain, such as the gate control theory [ 6 ] and pain matrix theory [ 7 ], involving advanced information conduction and processing, from the simple sensory input to neural network output of the central nervous system. Previous studies [ 5 , 6 , 7 , 8 , 9 ] revealed that PHN was closely associated with structural/microstructural and functional abnormalities in the brain mainly located in the ‘pain matrix’, including the primary somatosensory and secondary somatosensory, the thalamus, insula cortex, parahippocampal gyrus, amygdala, prefrontal cortices, as well as other regions, such as the precuneus, lentiform nucleus and brainstem, significantly affecting multiple dimensions of pain processing, including the sensory, affective, emotional, memory and cognitive aspects [ 10 ]. The pain matrix is considered as a characterization of brain regions associated with pain processing.…”

“…Animal models can avoid the above problems. Previous studies [ 8 , 9 , 16 ] have shown that a single systemic treatment of resiniferatoxin (RTX) could produce an interesting paradoxical change in thermal and mechanical sensitivities in adult rats, similar to the unique clinical features of patients with PHN. Pan [ 8 ] suggested that the diminished thermal sensitivity by RTX could be attributable to the depletion of unmyelinated afferent neurons.…”