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

• Published in: Neuroscience Vol. 193; pp. 440 - 451
• Main Authors: Chen, Y, Yang, C, Wang, Z.J
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 13-10-2011; Elsevier
• Subjects: Analysis of Variance; Anilides - pharmacology; Animals; Ankyrins - antagonists & inhibitors; Ankyrins - metabolism; Antineoplastic Agents, Phytogenic - toxicity; Biological and medical sciences; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Carbazoles - pharmacology; Central Nervous System - drug effects; Central Nervous System - metabolism; Cinnamates - pharmacology; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Estrenes - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Hyperalgesia - physiopathology; Male; mast cell tryptase; Mice; Mice, Inbred ICR; Neuralgia - chemically induced; Neuralgia - pathology; Neuralgia - physiopathology; Neurology; Oligopeptides - pharmacology; Paclitaxel - toxicity; paclitaxel-induced pain; Pain Measurement - methods; Physical Stimulation - adverse effects; Protein Kinase C - metabolism; Protein Kinase C - pharmacology; proteinase-activated receptor 2; Pyrroles - pharmacology; Pyrrolidinones - pharmacology; Receptor, PAR-2 - antagonists & inhibitors; Receptor, PAR-2 - metabolism; Sulfonamides - pharmacology; Time Factors; TRPA1; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism; TRPV1; TRPV4; Tryptases - metabolism; Type C Phospholipases - metabolism; Vertebrates: nervous system and sense organs; PAR; phospholipase C; TRP vanilloid 4; TRPA1; PLC; dorsal root ganglia; PKA; PKC; TRPV1; TRP vanilloid 1; proteinase-activated receptor 2; transient receptor potential; mast cell tryptase; TRP; TRPV4; proteinase-activated receptors; DRG; TRP ankyrin 1; paclitaxel-induced pain; protein kinase A; protein kinase C; Serine endopeptidases; Enzyme; Peptidases; TRPV1 vanilloid receptor; Pain; Paclitaxel; Tryptase; Hydrolases; Ankyrin; Vanilloid receptor; Biological receptor
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.06.085

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.