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Stimulating TRPV 1 externalization and synthesis in dorsal root ganglion neurons contributes to PGE 2 potentiation of TRPV 1 activity and nociceptor sensitization
Author(s) -
Ma W.,
StJacques B.,
Rudakou U.,
Kim Y.N.
Publication year - 2017
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.959
Subject(s) - trpv , dorsal root ganglion , chemistry , nociceptor , transient receptor potential channel , capsaicin , agonist , sensitization , trpv1 , hyperalgesia , pharmacology , endocrinology , microbiology and biotechnology , medicine , nociception , receptor , neuroscience , biochemistry , biology , sensory system
Background Persistent peripheral sensitization contributes to chronic pain. Plasticity of nociceptive dorsal root ganglion ( DRG ) neurons (nociceptors) induced by pro‐inflammatory mediators contributes to sensitization. Prostaglandin E2 ( PGE 2) enriched in injured tissues is known not only directly to sensitize DRG neurons, but also to potentiate sensitizing effects of other pain mediators such as capsaicin and its receptor transient receptor potential vanilloid‐1 ( TRPV 1). It remains unknown whether PGE 2 potentiates TRPV 1 activity by stimulating its synthesis, cell surface and axonal trafficking in DRG neurons. Methods Combined biochemical, morphological, pharmacological and behavioral approaches have been used to address this issue in both in vitro and in vivo models. Results PGE 2 increased TRPV 1 externalization in cultured rat DRG neurons in a time‐ and concentration‐dependent manner, an event blocked by an inhibitor of protein synthesis or anterograde export. EP 1 and EP 4, but not EP 2 and EP 3, mediated this event. EP 1 agonist‐induced TRPV 1 externalization was suppressed by inhibitors of Ca MKII , PLC , PKC and PKC ε, while EP 4 agonist‐induced TRPV 1 externalization by inhibitors of cAMP / PKA and ERK / MAPK . Pre‐exposure to PGE 2 potentiated release of calcitonin gene‐related peptide from cultured DRG neurons evoked by subsequent capsaicin stimulation. This event was blocked by an inhibitor of protein synthesis or export, suggesting that PGE 2‐induced TRPV 1 synthesis and externalization is coupled to enhanced TRPV 1 activity. Pre‐exposure to PGE 2 not only prolonged tactile allodynia evoked by subsequent capsaicin challenge, but also increased TRPV 1 levels in L4‐6 DRG , sciatic nerves and plantar skin. Conclusions Our data indicate that facilitating TRPV 1 synthesis, cell surface and axonal trafficking is a novel mechanism underlying PGE 2 potentiation of TRPV 1 activity.