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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.

SUBMITTER: Wei X

PROVIDER: S-EPMC8054387 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Postherpetic occipital neuralgia (PHON) is a neuropathic pain condition that usually presents as paroxysmal pain that is stabbing in nature.[5,7] It involves the occiput and posterior scalp in the distribution of the greater and/or lesser occipital nerves. It usually develops after an episode of shingles.[5,7] Treatment usually first consists of medical therapy and then progresses to invasive treatment (e.g., peripheral nerve stimulation, spinal cord epidural stimulation, C2-C3 ganglionectomy, or dorsal root entry zone [DREZ] rhizotomy).[1-4,6] Here, we present a case of persistent PHON that was treated with C1-C3 DREZ. Case Description: A 37-year-old female had a history of several episodes of shingles involving the left neck and occiput; they resolved after treatment with valacyclovir. Subsequently, however, she developed severe lancinating pain of the neck and the occiput and was diagnosed with PHON. Initially, she was treated with oxcarbazepine but was stopped due to cognitive side effects. She then had a cervical spinal cord stimulator implanted which produced relief for several years; it was later removed due to breakage of the electrodes. She then underwent a left- sided C1-C2 hemilaminectomy with a C1-C3 DREZ procedure.[1] Postoperatively, she had immediate resolution of her pain, but developed a new left hemiparesis (4+/5), accompanied by imbalance, decreased sensation to light touch, and loss of proprioception. On 6 weeks follow up, the pain was still relieved, and she exhibited significant improvement in her left-sided hemiparesis and hemisensory deficit to which returned to baseline. Similar outcome was maintained at four months follow up. Conclusion: Although high cervical DREZ lesions may effectively treat post herpetic/occipital neuralgia that fails other measures, there may be associated major neurological morbidity that makes this procedure acceptable as a salvage option, and after clearly explaining the risks to the patient.