| First Author | Zhang GF | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 27 | Pages | 5963-5978 |
| PubMed ID | 34252037 | Mgi Jnum | J:346219 |
| Mgi Id | MGI:6719510 | Doi | 10.1523/JNEUROSCI.0303-21.2021 |
| Citation | Zhang GF, et al. (2021) Alpha2delta-1 upregulation in primary sensory neurons promotes NMDA receptor-mediated glutamatergic input in resiniferatoxin-induced neuropathy. J Neurosci 41(27):5963-5978 |
| abstractText | 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 α2Ύ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2Ύ-1 and GluN1 in the spinal cord synaptosomes. RNAscope in situ hybridization showed that RTX treatment significantly increased α2Ύ-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 α2Ύ-1 with gabapentin, genetically ablating α2Ύ-1, or targeting α2Ύ-1-bound NMDA receptors with α2Ύ-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 α2Ύ-1 C terminus peptide reversed allodynia in RTX-treated rats and mice. In addition, RTX-induced tactile allodynia was attenuated in α2Ύ-1 knock-out mice and in mice in which GluN1 was conditionally knocked out in DRG neurons. Collectively, our findings indicate that α2Ύ-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.SIGNIFICANCE STATEMENT Postherpetic neuralgia (PHN), associated with shingles, is a distinct form of neuropathic pain commonly seen in elderly and immunocompromised patients. The synaptic plasticity underlying touch-induced pain hypersensitivity in PHN remains unclear. Using a nonviral animal model of PHN, we found that glutamatergic input from primary sensory nerves to the spinal cord is increased via tonic activation of glutamate NMDA receptors. Also, we showed that α2Ύ-1 (encoded by Cacna2d1), originally considered a calcium channel subunit, serves as an auxiliary protein that promotes activation of presynaptic NMDA receptors and pain hypersensitivity. This new information advances our understanding of the molecular mechanism underlying PHN and suggests new strategies for treating this painful condition. |
