title: The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4.
abstract: Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1(+) neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1(+) neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. Significance statement: In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.
authors.affiliation: Departments of Anesthesia and Pain Medicine.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Functional Morphology, Institute of Physiology, Academy of Sciences Czech Republic, 14220 Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Adamek
authors.affiliation: Department of Anesthesiology, University of Texas Medical School at Houston, Houston, Texas 77030.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Neurosurgery, and.
authors.forename: Claudio Esteves
authors.initials: CE
authors.lastname: Tatsui
authors.affiliation: Neurosurgery, and.
authors.forename: Laurence D
authors.identifier: http://orcid.org/0000-0002-8474-1521
authors.initials: LD
authors.lastname: Rhines
authors.affiliation: Department of Functional Morphology, Institute of Physiology, Academy of Sciences Czech Republic, 14220 Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Mrozkova
authors.affiliation: Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Kosturakis
authors.affiliation: University of Texas Health Science Center, Houston, Texas 77030.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Cassidy
authors.affiliation: Duke University School of Medicine, Durham, North Carolina 27710, and.
authors.forename: Daniel S
authors.identifier: http://orcid.org/0000-0001-5381-9878
authors.initials: DS
authors.lastname: Harrison
authors.affiliation: Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Cata
authors.affiliation: Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Sapire
authors.affiliation: Departments of Anesthesia and Pain Medicine.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: University of Texas Health Science Center, Houston, Texas 77030.
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kennamer-Chapman
authors.affiliation: University of Texas Health Science Center, Houston, Texas 77030.
authors.forename: Abdul Basit
authors.initials: AB
authors.lastname: Jawad
authors.affiliation: Anabios, Inc., San Diego, California 92109.
authors.forename: Andre
authors.initials: A
authors.lastname: Ghetti
authors.affiliation: Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Functional Morphology, Institute of Physiology, Academy of Sciences Czech Republic, 14220 Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Palecek
authors.affiliation: Departments of Anesthesia and Pain Medicine, pdougherty@mdanderson.org.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D051197:Toll-Like Receptor 4; D017239:Paclitaxel; D002118:Calcium
keywords: DRG; cancer; dorsal horn; neuropathy