title: Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain.
abstract: Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration of paclitaxel, mast cell tryptase activity was found to be increased in the spinal cord, dorsal root ganglia, and peripheral tissues in mice. FSLLRY-amide, a selective PAR2 antagonist, blocked paclitaxel-induced neuropathic pain behaviors in a dose- and time-dependent manner. In addition, blocking downstream signaling pathways of PAR2, including phospholipase C (PLC), protein kinase A (PKA), and protein kinase Cε (PKC), effectively attenuated paclitaxel-induced mechanical, heat, or cold hypersensitivity. Furthermore, sensitized pain response was selectively inhibited by antagonists of transient receptor potential (TRP) V1, TRPV4, or TRPA1. These results revealed specific cellular signaling pathways leading to paclitaxel-induced neuropathy, including the activation of PAR2 and downstream enzymes PLC, PKCε, and PKA and resultant sensitization of TRPV1, TRPV4, and TRPA1. Targeting one or more of these signaling molecules may present new opportunities for the treatment of paclitaxel-induced neuropathy.
authors.affiliation: Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017487:Ankyrins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology; D017239:Paclitaxel / Q000633:toxicity*; D010147:Pain Measurement / Q000379:methods; D010812:Physical Stimulation / Q000009:adverse effects; D011493:Protein Kinase C / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D053802:Tryptases / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000813:Anilides; C491707:Ank1 protein, mouse; D017487:Ankyrins; D000972:Antineoplastic Agents, Phytogenic; D002227:Carbazoles; D002934:Cinnamates; D004791:Enzyme Inhibitors; D004963:Estrenes; C508716:H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D009842:Oligopeptides; D011758:Pyrroles; D011760:Pyrrolidinones; C544743:RN 1734; D044464:Receptor, PAR-2; D013449:Sulfonamides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D053802:Tryptases; C071423:capsazepine; D017239:Paclitaxel; D002211:Capsaicin