a2d-1 upregulation in primary sensory neurons promotes NMDA receptor-mediated glutamatergic input in resiniferatoxin-induced neuropathy

Guang Fen Zhang, Shao-Rui Chen, Daozhong Jin, Yuying Huang, Hong Chen, Hui-Lin Pan

Research output: Contribution to journalArticlepeer-review

Abstract

Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with a2d-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between a2d-1 and GluN1 in the spinal cord synaptosomes. RNAscope in situ hybridization showed that RTX treatment significantly increased a2d-1 expression in DRG neurons labeled with calcitonin gene-related peptide, isolectin B4, NF200, and tyrosine hydroxylase. Electrophysiological recordings revealed that RTX treatment augmented the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of evoked EPSCs in spinal dorsal horn neurons, and these effects were reversed by blocking NMDA receptors with AP-5. Inhibiting a2d-1 with gabapentin, genetically ablating a2d-1, or targeting a2d-1–bound NMDA receptors with a2d-1Tat peptide largely normalized the baseline frequency of mEPSCs and the amplitude of evoked EPSCs potentiated by RTX treatment. Furthermore, systemic treatment with memantine or gabapentin and intrathecal injection of AP-5 or Tat-fused a2d-1 C terminus peptide reversed allodynia in RTX-treated rats and mice. In addition, RTX-induced tactile allodynia was attenuated in a2d-1 knock-out mice and in mice in which GluN1 was conditionally knocked out in DRG neurons. Collectively, our findings indicate that a2d-1–bound NMDA receptors at presynaptic terminals of sprouting myelinated afferent nerves contribute to RTX-induced potentiation of nociceptive input to the spinal cord and tactile allodynia.

Original languageEnglish (US)
Pages (from-to)5963-5978
Number of pages16
JournalJournal of Neuroscience
Volume41
Issue number27
DOIs
StatePublished - Jul 7 2021

Keywords

  • Dorsal root ganglion
  • Gabapentinoid
  • Neuropathic pain
  • NMDA receptor
  • Pregabalin
  • Spinal cord
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

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