Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons.
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.
University of Louisville, Department of Anesthesiology, Louisville, KY, United States; University of Louisville, Department of Anatomical Sciences and Neurobiology, Louisville, KY, United States; University of Louisville, KY Spinal Cord Injury Research Center, Louisville, KY, United States.
Kristofer K
KK
Rau
Burke Medical Research Institute, White Plains, NY, United States; Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States.
Caitlin E
CE
Hill
University of Louisville, Department of Anatomical Sciences and Neurobiology, Louisville, KY, United States; University of Louisville, KY Spinal Cord Injury Research Center, Louisville, KY, United States; University of Louisville, KY Biomedical Research Infrastructure Network (KBRIN), Louisville, KY, United States.
Benjamin J
BJ
Harrison
University of Louisville, Department of Anatomical Sciences and Neurobiology, Louisville, KY, United States; University of Louisville, KY Spinal Cord Injury Research Center, Louisville, KY, United States.
Gayathri
G
Venkat
University of Louisville, Department of Anesthesiology, Louisville, KY, United States.
Heidi M
HM
Koenig
Burke Medical Research Institute, White Plains, NY, United States.
Sarah B
SB
Cook
University of Kentucky, Department of Physiology, Lexington, KY, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, Lexington, KY, United States.
Alexander G
AG
Rabchevsky
University of Kentucky, Department of Physiology, Lexington, KY, United States.
Bradley K
BK
Taylor
Ohio State University, Department of Molecular and Cellular Biochemistry, Columbus, OH, United States.
Tsonwin
T
Hai
University of Louisville, Department of Anatomical Sciences and Neurobiology, Louisville, KY, United States; University of Louisville, KY Spinal Cord Injury Research Center, Louisville, KY, United States; University of Louisville, KY Biomedical Research Infrastructure Network (KBRIN), Louisville, KY, United States; University of Louisville, Department of Neurological Surgery, Louisville, KY, United States. Electronic address: j.petruska@louisville.edu.
Jeffrey C
JC
Petruska
D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007839:Functional Laterality; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D059225:Nociception / Q000502:physiology*; D059226:Nociceptive Pain / Q000209:etiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism*; D012871:Skin Diseases / Q000150:complications* / Q000473:pathology*; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D053675:Versicans
D019922:GAP-43 Protein; D006023:Glycoproteins; D037102:Lectins; D009478:Neuropeptide Y; D012333:RNA, Messenger; D058127:Transcription Factor 3; C508324:Vcan protein, rat; D053675:Versicans; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517686:Camk4 protein, rat
Cell stress; Dorsal root ganglion; Nociceptor; Pain; Tissue damage