Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons

Kristofer K. Rau, Caitlin E. Hill, Benjamin J. Harrison, Gayathri Venkat, Heidi M. Koenig, Sarah B. Cook, Alexander G. Rabchevsky, Bradley K. Taylor, Tsonwin Hai, Jeffrey C. Petruska

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Tissue damage is one of the major etiological factors in the emergence of chronic/persistent pain, although mechanisms remain enigmatic. Using incision of the back skin of adult rats as a model for tissue damage, we observed sensitization in a nociceptive reflex enduring to 28 days post-incision (DPI). To determine if the enduring behavioral changes corresponded with a long-term impact of tissue damage on sensory neurons, we examined the temporal expression profile of injury-regulated genes and the electrophysiological properties of traced dorsal root ganglion (DRG) sensory neurons. The mRNA for the injury/stress-hub gene Activating Transcription Factor 3 (ATF3) was upregulated and peaked within 4 DPI, after which levels declined but remained significantly elevated out to 28 DPI, a time when the initial incision appears healed and tissue-inflammation largely resolved. Accordingly, stereological image analysis indicated that some neurons expressed ATF3 only transiently (mostly medium-large neurons), while in others it was sustained (mostly small neurons), suggesting cell-type-specific responses. In retrogradely-traced ATF3-expressing neurons, Calcium/calmodulin-dependent protein kinase type IV (CAMK4) protein levels and isolectin-B4 (IB4)-binding were suppressed whereas Growth Associated Protein-43 (GAP-43) and Neuropeptide Y (NPY) protein levels were enhanced. Electrophysiological recordings from DiI-traced sensory neurons 28 DPI showed a significant sensitization limited to ATF3-expressing neurons. Thus, ATF3 expression is revealed as a strong predictor of single cells displaying enduring pain-related electrophysiological properties. The cellular injury/stress response induced in sensory neurons by tissue damage and indicated by ATF3 expression is positioned to contribute to pain which can occur after tissue damage.

Original languageEnglish
Pages (from-to)413-427
Number of pages15
JournalExperimental Neurology
StatePublished - Sep 1 2016

Bibliographical note

Funding Information:
The authors thank the staff of the KY Spinal Cord Injury Research Center (KSCIRC) for support, particularly Darlene Burke for statistical consultation. This study was supported by the Kentucky Spinal Cord and Head Injury Research Trust ( 09-12A to JCP, 10-10 to JCP and AGR), the Kentucky Spinal Cord Injury Research Center Traineeship (to KKR), the Burke Foundation (CEH, SBC), Paralyzed Veterans of America Fellowship ( #2579 to BJH), NIH ( R21NS080091 to JCP and TH, R01NS094741 to JCP), and the Core facilities of the Kentucky Spinal Cord Injury Research Center ( P30GM103507 to Scott Whittemore). The authors declare no competing financial interests.

Publisher Copyright:
© 2016 Elsevier Inc.


  • Cell stress
  • Dorsal root ganglion
  • Nociceptor
  • Pain
  • Tissue damage

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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