Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion

Elizabeth Salvo, Wendy M. Campana, Nicole N. Scheff, Tu Huu Nguyen, Se Hee Jeong, Ian Wall, Angie K. Wu, Susanna Zhang, Hyesung Kim, Aditi Bhattacharya, Malvin N. Janal, Cheng Liu, Donna G. Albertson, Brian Schmidt, John Dolan, Robert E. Schmidt, M. Danilo Boada, Yi Ye

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here, we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting that unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. Perineural invasion induced afterdischarge in A high-threshold mechanoreceptors (HTMRs), mechanical sensitization (ie, decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low-threshold mechanoreceptors. Perineural invasion resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically insensitive and electrically unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.

Original languageEnglish (US)
Pages (from-to)2592-2602
Number of pages11
JournalPain
Volume161
Issue number11
DOIs
StatePublished - Nov 1 2020

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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