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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / pharmacology
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Anilides / pharmacology
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Animals
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Arachidonic Acids / pharmacology
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Blotting, Western
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Calcium / metabolism
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Capsaicin / pharmacology
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Cells, Cultured
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Cinnamates / pharmacology
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Cytokines / genetics
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Cytokines / metabolism
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Dinoprostone / metabolism
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Dose-Response Relationship, Drug
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Endocannabinoids
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Ganglia, Spinal / cytology
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Humans
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Imidazoles / pharmacology
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Mice
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Microscopy, Confocal
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Neurons / drug effects*
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Neurons / metabolism
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Pain / physiopathology*
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Poly I-C / pharmacology
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Polyunsaturated Alkamides / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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TRPV Cation Channels / antagonists & inhibitors
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TRPV Cation Channels / metabolism
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Toll-Like Receptor 3 / metabolism
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Toll-Like Receptor 7 / metabolism
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Toll-Like Receptor 9 / metabolism
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Toll-Like Receptors / agonists
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Toll-Like Receptors / metabolism*
Substances
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Aminoquinolines
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Anilides
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Arachidonic Acids
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Cinnamates
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Cytokines
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Endocannabinoids
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Imidazoles
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N-(3-methoxyphenyl)-4-chlorocinnamanilide
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Polyunsaturated Alkamides
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TRPV Cation Channels
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TRPV1 receptor
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Toll-Like Receptor 3
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Toll-Like Receptors
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gardiquimod
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Dinoprostone
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Poly I-C
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Capsaicin
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Calcium
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anandamide