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.

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

10.21203/rs.3.rs-116000/v1 ◽

2020 ◽

Author(s):

Xiang Wei ◽

Lina Wang ◽

Jie Hua ◽

Xiao-hong Jin ◽

Fuhai Ji ◽

...

Keyword(s):

Inflammatory Response ◽

Protein Expression ◽

Dorsal Root Ganglia ◽

Postherpetic Neuralgia ◽

Dorsal Root ◽

Mechanical Allodynia ◽

Neuronal Excitability ◽

Thermal Hyperalgesia ◽

Varicella Zoster Virus Infection ◽

Pc 12 Cells

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.

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Morphological and electrophysiological changes in mouse dorsal root ganglia after partial colonic obstruction

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00028.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. G670-G678 ◽

Cited By ~ 36

Author(s):

Tian-Ying Huang ◽

Menachem Hanani

Keyword(s):

Glial Cells ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neuronal Excitability ◽

Colonic Obstruction ◽

Resting Potential ◽

Dye Coupling ◽

Drg Neurons ◽

Satellite Glial Cells ◽

Colon Wall

There is evidence that sensitization of neurons in dorsal root ganglia (DRG) may contribute to pain induced by intestinal injury. We hypothesized that obstruction-induced pain is related to changes in DRG neurons and satellite glial cells (SGCs). In this study, partial colonic obstruction was induced by ligation. The neurons projecting to the colon were traced by an injection of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate into the colon wall. The electrophysiological properties of DRG neurons were determined using intracellular electrodes. Dye coupling was examined with an intracellular injection of Lucifer yellow (LY). Morphological changes in the colon and DRG were examined. Pain was assessed with von Frey hairs. Partial colonic obstruction caused the following changes. First, coupling between SGCs enveloping different neurons increased 18-fold when LY was injected into SGCs near neurons projecting to the colon. Second, neurons were not coupled to other neurons or SGCs. Third, the firing threshold of neurons projecting to the colon decreased by more than 40% ( P < 0.01), and the resting potential was more positive by 4–6 mV ( P < 0.05). Finally, the number of neurons displaying spontaneous spikes increased eightfold, and the number of neurons with subthreshold voltage oscillations increased over threefold. These changes are consistent with augmented neuronal excitability. The pain threshold to abdominal stimulation decreased by 70.2%. Inflammatory responses were found in the colon wall. We conclude that obstruction increased neuronal excitability, which is likely to be a major factor in the pain behavior observed. The augmented dye coupling between glial cells may contribute to the neuronal hyperexcitability.

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Calcitonin gene-related peptide-receptor component protein expression in the uterine cervix, lumbosacral spinal cord, and dorsal root ganglia

Peptides ◽

10.1016/s0196-9781(01)00638-6 ◽

2002 ◽

Vol 23 (3) ◽

pp. 507-514 ◽

Cited By ~ 20

Author(s):

M.J Pokabla ◽

I.M Dickerson ◽

R.E Papka

Keyword(s):

Spinal Cord ◽

Protein Expression ◽

Dorsal Root Ganglia ◽

Uterine Cervix ◽

Dorsal Root ◽

Lumbosacral Spinal Cord ◽

Peptide Receptor ◽

Receptor Component ◽

Calcitonin Gene ◽

Component Protein

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Liver X Receptors Protect Dorsal Root Ganglia from Obesity-Induced Endoplasmic Reticulum Stress and Mechanical Allodynia

Cell Reports ◽

10.1016/j.celrep.2018.09.046 ◽

2018 ◽

Vol 25 (2) ◽

pp. 271-277.e4 ◽

Cited By ~ 17

Author(s):

Chaitanya K. Gavini ◽

Angie L. Bookout ◽

Raiza Bonomo ◽

Laurent Gautron ◽

Syann Lee ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Mechanical Allodynia ◽

Liver X Receptors ◽

X Receptors

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Purinergic signaling between neurons and satellite glial cells of mouse dorsal root ganglia modulates neuronal excitability in vivo

Pain ◽

10.1097/j.pain.0000000000002556 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Zhiyong Chen ◽

Qian Huang ◽

Xiaodan Song ◽

Neil C. Ford ◽

Chi Zhang ◽

...

Keyword(s):

Glial Cells ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neuronal Excitability ◽

Purinergic Signaling ◽

Satellite Glial Cells

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Anion exchanger 3 in dorsal root ganglion contributes to nerve injury-induced chronic mechanical allodynia and thermal hyperalgesia

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12868 ◽

2018 ◽

Vol 70 (3) ◽

pp. 374-382 ◽

Cited By ~ 1

Author(s):

Marian J. Pérez-Rodríguez ◽

Isabel Velazquez-Lagunas ◽

Alejandro Pluma-Pluma ◽

Paulino Barragán-Iglesias ◽

Vinicio Granados-Soto

Keyword(s):

Dorsal Root Ganglion ◽

Nerve Injury ◽

Anion Exchanger ◽

Dorsal Root ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia

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Time Course of Inflammation in Dorsal Root Ganglia Correlates with Differential Reversibility of Mechanical Allodynia

Neuroscience ◽

10.1016/j.neuroscience.2019.12.040 ◽

2020 ◽

Vol 428 ◽

pp. 199-216 ◽

Cited By ~ 3

Author(s):

Myung-chul Noh ◽

Benjamin Mikler ◽

Twinkle Joy ◽

Peter A. Smith

Keyword(s):

Dorsal Root Ganglia ◽

Dorsal Root ◽

Mechanical Allodynia ◽

Time Course

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Melatonin Reduces Excitability in Dorsal Root Ganglia Neurons with Inflection on the Repolarization Phase of the Action Potential

International Journal of Molecular Sciences ◽

10.3390/ijms20112611 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2611 ◽

Cited By ~ 2

Author(s):

Klausen Oliveira-Abreu ◽

Nathalia Silva-dos-Santos ◽

Andrelina Coelho-de-Souza ◽

Francisco Ferreira-da-Silva ◽

Kerly Silva-Alves ◽

...

Keyword(s):

Action Potential ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neuronal Excitability ◽

Input Resistance ◽

Cell Types ◽

Neuronal Population ◽

Resting Membrane Potential ◽

Electrophysiological Properties ◽

Repolarization Phase

Melatonin is a neurohormone produced and secreted at night by pineal gland. Many effects of melatonin have already been described, for example: Activation of potassium channels in the suprachiasmatic nucleus and inhibition of excitability of a sub-population of neurons of the dorsal root ganglia (DRG). The DRG is described as a structure with several neuronal populations. One classification, based on the repolarizing phase of the action potential (AP), divides DRG neurons into two types: Without (N0) and with (Ninf) inflection on the repolarization phase of the action potential. We have previously demonstrated that melatonin inhibits excitability in N0 neurons, and in the present work, we aimed to investigate the melatonin effects on the other neurons (Ninf) of the DRG neuronal population. This investigation was done using sharp microelectrode technique in the current clamp mode. Melatonin (0.01–1000.0 nM) showed inhibitory activity on neuronal excitability, which can be observed by the blockade of the AP and by the increase in rheobase. However, we observed that, while some neurons were sensitive to melatonin effect on excitability (excitability melatonin sensitive—EMS), other neurons were not sensitive to melatonin effect on excitability (excitability melatonin not sensitive—EMNS). Concerning the passive electrophysiological properties of the neurons, melatonin caused a hyperpolarization of the resting membrane potential in both cell types. Regarding the input resistance (Rin), melatonin did not change this parameter in the EMS cells, but increased its values in the EMNS cells. Melatonin also altered several AP parameters in EMS cells, the most conspicuously changed was the (dV/dt)max of AP depolarization, which is in coherence with melatonin effects on excitability. Otherwise, in EMNS cells, melatonin (0.1–1000.0 nM) induced no alteration of (dV/dt)max of AP depolarization. Thus, taking these data together, and the data of previous publication on melatonin effect on N0 neurons shows that this substance has a greater pharmacological potency on Ninf neurons. We suggest that melatonin has important physiological function related to Ninf neurons and this is likely to bear a potential relevant therapeutic use, since Ninf neurons are related to nociception.

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