Weiya Ma
McGill University, Canada
Title: Facilitating synthesis, axonal and cell surface trafficking of EP4 receptor and TRPV1 channel contributes to PGE2-induced nociceptor sensitization and transition from acute to chronic pain
Biography
Biography: Weiya Ma
Abstract
Chronic pain is an unmet clinical need which severely deteriorates the quality of life of individuals and imposes heavy financial burden on the health care system. Its treatment is rather challenging due to the unclear underlying mechanism. Growing evidence indicates that peripheral (nociceptor) and central sensitization caused by inflammatory mediators plays an essential role in the genesis of chronic pain. Pain mediator prostaglandin E2 (PGE2) abundantly produced in inflamed tissues is known to sensitize dorsal root ganglion (DRG) neurons and potentiates sensitizing effects of other pain mediators such as capsaicin and its receptor, transient receptor potential vanilloid-1 (TRPV1). We hypothesized that facilitating the long-term synthesis, axonal and cell surface trafficking of PGE2/EP4 receptor and capsaicin/TRPV1 channel in DRG neuronsis involved in nociceptor sensitization and transition from acute to chronic pain. In cultured DRG neurons, PGE2 and EP4 agonist increased cell surface trafficking of EP4 receptor and TRPV1 channel, events mediated through PKA and PKC signaling transduction pathways and coupled with enhanced nociceptive activities of EP4 and TRPV1. In a model of transition from acute to chronic pain, pre-exposure to PGE2 prolonged mechanical allodynia evoked by subsequent PGE2 or capsaicin challenge. This event was blocked by pre-injection of EP4 antagonist. Intraplanar (i.pl.) injection of PGE2 increased the levels of EP4 and TRPV1 in DRG neurons, sciatic nerves and plantarskin, which was suppressed by co-injection of EP4 antagonist. In inflammatory pain models, i.pl.co-injection of COX2 inhibitor or EP4 antagonists with carrageenan or complete Freud’s adjuvant blocked or shortened mechanical allodynia evoked by subsequent PGE2 challenge. Inflammation-increased EP4 and TRPV1 in DRG neurons were reversed by COX2 inhibitor or EP4 antagonists. These data suggest facilitating synthesis, axonal trafficking and cell surface trafficking of EP4 and TRPV1 through PGE2/EP4 signaling contributes to nociceptor sensitization and potentiation as well as transition from acute to chronic pain.