title: Painful pathways induced by TLR stimulation of dorsal root ganglion neurons.
abstract: We hypothesize that innate immune signals from infectious organisms and/or injured tissues may activate peripheral neuronal pain signals. In this study, we demonstrated that TLRs 3, 7, and 9 are expressed by human dorsal root ganglion neurons (DRGNs) and in cultures of primary mouse DRGNs. Stimulation of murine DRGNs with TLR ligands induced expression and production of proinflammatory chemokines and cytokines CCL5 (RANTES), CXCL10 (IP-10), IL-1α, IL-1β, and PGE(2), which have previously been shown to augment pain. Further, TLR ligands upregulated the expression of a nociceptive receptor, transient receptor potential vanilloid type 1 (TRPV1), and enhanced calcium flux by TRPV1-expressing DRGNs. Using a tumor-induced temperature sensitivity model, we showed that in vivo administration of a TLR9 antagonist, known as a suppressive oligodeoxynucleotide, blocked tumor-induced temperature sensitivity. Taken together, these data indicate that stimulation of peripheral neurons by TLR ligands can induce nerve pain.
authors.affiliation: Laboratory of Molecular Immunoregulation, Cancer and Inflammatory Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Qi
authors.forename: Krisztina
authors.initials: K
authors.lastname: Buzas
authors.forename: Huiting
authors.initials: H
authors.lastname: Fan
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Cohen
authors.forename: Kening
authors.initials: K
authors.lastname: Wang
authors.forename: Erik
authors.initials: E
authors.lastname: Mont
authors.forename: Dennis
authors.initials: D
authors.lastname: Klinman
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000503:physiopathology*; D011070:Poly I-C / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D000813:Anilides; D001095:Arachidonic Acids; D002934:Cinnamates; D016207:Cytokines; D063388:Endocannabinoids; D007093:Imidazoles; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C546771:gardiquimod; D015232:Dinoprostone; D011070:Poly I-C; D002211:Capsaicin; D002118:Calcium; C078814:anandamide