Epac and nociceptor sensitization

Abstract

Primary sensory neurons are responsible for transmitting sensory information from the peripheral to the central nervous system. Their responses to incoming stimulation become greatly enhanced and prolonged following inflammation, giving rise to exaggerated nociceptive responses and chronic pain. The inflammatory mediator, prostaglandin E2 (PGE2), released from the inflamed tissue surrounding the terminals of sensory neurons contributes to the abnormal pain responses. PGE2 acts on G protein-coupled EP receptors to activate adenylyl cyclase, which catalyzes the conversion of adenosine triphosphate to cyclic adenosine 3′,5′-monophosphate (cAMP). Under normal conditions, cAMP activates primarily protein kinase A. After inflammation, cAMP also activates the exchange proteins activated by cAMP (Epacs) to produce exaggerated PGE2-mediated hyperalgesia. The role of cAMP-Epac signaling in the generation of hypersensitivity is the topic of this review.

Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1

“…Because we did not detect a role for PKA we also investigated two additional proteins that can respond to increased levels of cAMP and mediate downstream signaling responses (see Figure 1B ); EPAC1/Rapgef1 (inhibited by ESI09) and EPAC2/Rapgef2 (inhibited by SQ22,536). Downstream targets of EPAC1 1 and 2 include ERK and PKC respectively ( Huang and Gu, 2017 ). However, inhibition of EPAC1 with ESI09 did not inhibit forskolin-mediated reactivation ( Figure 2—figure supplement 2E ).…”

Signalling transduction events involved in agonist‐induced PGE2/EP4 receptor externalization in cultured rat dorsal root ganglion neurons

“…Two variants, Epac1 and Epac2, couple cAMP to activate Rap, through which cAMP influences diverse cellular processes (Holz et al., ) including exocytosis or externalization (Bos, ). Recent evidence showed that cAMP/Epac signalling plays an important role in chronic pain by sensitizing nociceptors (Singhmar et al., ; Huang and Gu, ; Matsuda et al., ) cAMP/Epac has been shown to mediate numerous functions of EP4 activation (Yokoyama et al., ). In the present study, we found that cAMP/Epac activator 8‐pCPT in a concentration‐dependent manner increased EP4 externalization, suggesting that in parallel with cAMP/PKA, cAMP/Epac signalling is also involved in agonist‐induced EP4 externalization.…”

Propofol attenuates postoperative hyperalgesia via regulating spinal GluN2B‐p38MAPK/EPAC1 pathway in an animal model of postoperative pain

“…Intraplantar injection of the EPAC agonists led to long‐lasting mechanical hyperalgesia (Hucho et al, ). Moreover, the expression of EPAC1 and EPAC2 markedly increased at the time when nociceptive hypersensitivity developed after plantar incision (Huang & Gu, ; Mizukoshi et al, ). Particularly interesting, genetic deletion of EPAC1 protected against inflammation‐induced mechanical hyperalgesia, whereas selective EPAC1 inhibition prevented or reversed existing inflammation or incision‐induced nociceptive hypersensitivity without affecting normal pain sensitivity (Hucho et al, ; Singhmar et al, ).…”