Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Carmen W Dessauer
Edgar T Walters
Shane R Cunha
Juan J Herrera
Chronic pain is a major complaint of those living with spinal cord injury (SCI), affecting 65-80% of the SCI population, but the treatment options remain limited or non-existent. The cAMP sensor EPAC has previously been shown to play a key role in chronic inflammatory and neuropathic pain, though the contribution from each of its two main isoforms, EPAC1 and EPAC2, is unclear. Here I test the hypothesis that both EPAC1 and EPAC2 play a key role in the maintenance of persistent nociceptor hyperexcitability and chronic pain after SCI.
Using both a T9 SCI mouse model and a T10 SCI rat model, we employed behavior assays and electrophysiological techniques to characterize the role of EPAC1 and 2 in SCI-induced pain. We also used three novel methods: the operant mechanical conflict test (MC) behavior test, an electrophysiological measure of ongoing activity (OA), and analysis of the transient depolarizing fluctuations (DSFs) in membrane potential that contribute to nociceptor excitability.
After SCI, we observed a significant increase in the incidence of SA, large DSFs, and OA in WT, Epac2-/-, and Epac1-/- mice. The SCI-induced increase in SA and OA incidence could be significantly decreased in nociceptors isolated from Epac1-/- and Epac2-/- mice by inhibition of the complementary EPAC isoform. Behavioral measures of “pain” did not show significant differences between WT and EPAC2-/- mice in a naïve state or after injury. Additionally, multi-day treatment with ESI-09, an inhibitor of both Epac1 and 2, caused a significant decrease in mechanical sensitivity within WT and Epac2-/- mice; however, in vitro treatment with ESI-09 resulted in mass electrophysiological silencing of nociceptors, suggesting the decrease in sensitivity was due to nociceptor cell silencing in vivo.
The data shows compensatory and/or redundant functions for EPAC1 and EPAC2. Importantly, future studies and attempts to develop chronic pain therapies may need to account for both isoforms of EPAC and their complementary roles.
Exchange protein activated by cAMP, cyclic adenosine monophosphate, spontaneous activity, ongoing activity, spinal cord injury, operant behavior test, hyperalgesia
Available for download on Friday, December 13, 2019