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

TitleCutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons.
Publication TypeJournal Article
Year of Publication2016
AuthorsRau KK, Hill CE, Harrison BJ, Venkat G, Koenig HM, Cook SB, Rabchevsky AG, Taylor BK, Hai T, Petruska JC
JournalExp Neurol
IssuePt A
Date Published2016 Sep
KeywordsAnimals, Calcium-Calmodulin-Dependent Protein Kinase Type 4, Disease Models, Animal, Female, Functional Laterality, Ganglia, Spinal, GAP-43 Protein, Glycoproteins, Lectins, Neuropeptide Y, Nociception, Nociceptive Pain, Rats, Rats, Sprague-Dawley, RNA, Messenger, Sensory Receptor Cells, Skin Diseases, Transcription Factor 3, Up-Regulation

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 28days 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.

Alternate JournalExp. Neurol.
PubMed ID27264359
PubMed Central IDPMC4992590
Grant ListR01 NS094741 / NS / NINDS NIH HHS / United States
P20 RR016481 / RR / NCRR NIH HHS / United States
R01 DA037621 / DA / NIDA NIH HHS / United States
P30 GM103507 / GM / NIGMS NIH HHS / United States
P20 GM103436 / GM / NIGMS NIH HHS / United States
R21 NS080091 / NS / NINDS NIH HHS / United States