title: Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors.
abstract: Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor sensitization. Blocking COX2/PGE2/EP4 signaling at an earlier stage of inflammation or injury is crucial for preventing the transition from acute pain to a chronic state.
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: St-Jacques
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada; Department of Psychiatry, McGill University, Montréal, Québec H4H 1R3, Canada. Electronic address: weiya.ma@douglas.mcgill.ca.
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000633:toxicity; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology*; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013997:Time Factors; D053675:Versicans
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; D037102:Lectins; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C508324:Vcan protein, rat; D053675:Versicans; D015064:16,16-Dimethylprostaglandin E2
keywords: 16,16-dimethyl PGE2; Anterograde axonal transport; COX2; Dorsal root ganglion; EP receptor; Intraplantar injection; Nociceptor; PGE2; Sensitization; Tactile allodynia