Journal
PAIN
Volume 161, Issue 11, Pages 2592-2602Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000001986
Keywords
Oral cancer pain; Perineural invasion; Nerve injury; Sensitization; Nociceptors; HTMRs; LTMRs; Schwann cells
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Funding
- Rita Allen Foundation
- NIH [R01DE029493, R03DE027777, R01DE019796, R21DE026964, R01DE026806, R01CA113833, R21CA163019]
- Laura and Isaac Perlmutter Cancer Center [P30CA016087]
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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.
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