Role of exchange protein directly activated by cAMP 1 & 2 (Epac1 & Epac2) in inflammatory pain

Abstract

3’-5’-cyclic adenosine monophosphate (cAMP) is a key mediator of nociceptor signaling. There is evidence that Epac mediates cAMP signaling under inflammatory conditions, however, the significance of the two isoforms of Epac, Epac1 and Epac2, in inflammatory pain is unclear. In the present study, Epac1 (Epac1-/-) and Epac2 (Epac2-/-)-deficient mice were used to study the role of Epac in formalin-induced inflammatory pain. Here, we report that Epac1-/- and Epac2-/- mice display significantly lower nociceptor behavior compared to the wild-type (Epac1+/+; 2+/+) mice under formalin-induced inflammatory conditions. Cyclooxygenase-2 (Cox-2) protein was significantly overexpressed in the ipsilateral sciatic nerve of the Epac1+/+; 2+/+, but not Epac2-/- mice. Cox-2 is rapidly induced due to inflammation and is known to sensitize nociceptors leading to increased pain sensitivity. Collectively, these data suggest that Epac2 deficiency alleviates pain by preventing Cox2 induction. Furthermore, phosphorylated ERK protein expression was found to be significantly reduced in the ipsilateral DRG of Epac2-/- mice, suggesting that the Epac2 deficiency leads to suppression of formalin-induced ERK phosphorylation in the DRG. Our findings indicate the involvement of both Epac1 and Epac2 in inflammation-induced hyperalgesia in animals, and suggest that Epac could potentially be a novel therapeutic target for the treatment of pain.